Journal Articles

CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming

Spotlight 

(1) Venzin V (2) Beccaria CG (3) Perucchini C (4) Delfino P (5) Bono EB (6) Giustini L (7) Moalli F (8) Grillo M (9) Fumagalli V (10) Laura C (11) Di Lucia P (12) Reinhard K (13) Petschenka J (14) Omokoko TA (15) Celant A (16) Ottolini S (17) Kawashima K (18) Ravˆ M (19) De Giovanni M (20) Inverso D (21) Kuka M (22) Kennedy PTF (23) Guilliams M (24) Casorati G (25) Pedica F (26) Ponzoni M (27) _ahin U (28) Le Bert N (29) Bertoletti A (30) Vascotto F (31) Guidotti LG (32) Iannacone M

Nature immunology

Venzin and Beccaria et al. demonstrate that pre-activated CD4+ T cells actively license local hepatic APCs and restore antiviral CD8+ T cell function. HBV-specific CD4+ T cell receptor transgenic mice show that effector CD4+ T cells reprogram Kupffer cells (KCs), but not DCs, to rescue dysfunctional CD8+ T cells in a tolerogenic hepatic environment. CD4+ T cells activated KCs via CD40L-CD40 interactions prompting IL-12 and IL-27 production. IL-12 amplified the helper CD4+ T cells and IL-27 reinvigorated dysfunctional CD8+ T cells. Exogenous IL-27 reinstated HBV-specific CD8+ T cell effector function in T cells from chronically infected patients.

Contributed by Shishir Pant

(1) Venzin V (2) Beccaria CG (3) Perucchini C (4) Delfino P (5) Bono EB (6) Giustini L (7) Moalli F (8) Grillo M (9) Fumagalli V (10) Laura C (11) Di Lucia P (12) Reinhard K (13) Petschenka J (14) Omokoko TA (15) Celant A (16) Ottolini S (17) Kawashima K (18) Ravˆ M (19) De Giovanni M (20) Inverso D (21) Kuka M (22) Kennedy PTF (23) Guilliams M (24) Casorati G (25) Pedica F (26) Ponzoni M (27) _ahin U (28) Le Bert N (29) Bertoletti A (30) Vascotto F (31) Guidotti LG (32) Iannacone M

Nature immunology

Venzin and Beccaria et al. demonstrate that pre-activated CD4+ T cells actively license local hepatic APCs and restore antiviral CD8+ T cell function. HBV-specific CD4+ T cell receptor transgenic mice show that effector CD4+ T cells reprogram Kupffer cells (KCs), but not DCs, to rescue dysfunctional CD8+ T cells in a tolerogenic hepatic environment. CD4+ T cells activated KCs via CD40L-CD40 interactions prompting IL-12 and IL-27 production. IL-12 amplified the helper CD4+ T cells and IL-27 reinvigorated dysfunctional CD8+ T cells. Exogenous IL-27 reinstated HBV-specific CD8+ T cell effector function in T cells from chronically infected patients.

Contributed by Shishir Pant

ABSTRACT: Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.

Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2)

Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (3) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (4) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (5) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (7) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (8) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (9) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (10) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. (11) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (12) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (13) Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. (14) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (15) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (16) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. Department of Molecular Medicine, University of Pavia, Pavia, Italy. (17) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (18) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (19) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (20) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (21) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (22) Department of Hepatology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (23) Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium. Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium. (24) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (25) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (26) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (27) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (28) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (29) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (30) TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (31) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (32) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it. Vita-Salute San Raffaele University, Milan, Italy. iannacone.matteo@hsr.it. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it.

Citation: Nat Immunol 2025 Jun 30 Epub06/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40588520

Tags:

Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants Featured  

(1) Revach OY (2) Cicerchia AM (3) Shorer O (4) Palin CA (5) Petrova B (6) Anderson S (7) Liu B (8) Park J (9) Chen L (10) Mehta A (11) Wright SJ (12) McNamee N (13) Tal-Mason A (14) Cattaneo G (15) Tiwari P (16) Xie H (17) Sweere JM (18) Cheng LC (19) Sigal N (20) Enrico E (21) Miljkovic M (22) Evans SA (23) Nguyen N (24) Whidden ME (25) Srinivasan R (26) Spitzer MH (27) Sun Y (28) Sharova T (29) Lawless AR (30) Michaud WA (31) Rasmussen MQ (32) Fang J (33) Brook JR (34) Chen F (35) Wang X (36) Ferrone CR (37) Lawrence DP (38) Sullivan RJ (39) Liu D (40) Sachdeva UM (41) Sen DR (42) Flaherty KT (43) Manguso RT (44) Bod L (45) Kellis M (46) Boland GM (47) Yizhak K (48) Yang J (49) Kanarek N (50) Sade-Feldman M (51) Hacohen N (52) Jenkins RW

Cell reports. Medicine

Revach et al. recently showed that in melanoma and other cancers, chronic TCR stimulation and type I IFN signaling in the tumor induced upregulation of CD38 (an ecto-enzyme involved in NAD+ catabolism) in CD8+ T cells in tumors. This drove a reduction in NAD+, leading to an impaired metabolic state and T cell dysfunction associated with resistance to ICB. Disrupting CD38 restored NAD+ pools and mitochondrial function, improved T cell function, and restored ICB sensitivity in melanoma organotypic tumor spheroids derived from patients with ICB-resistant melanoma.

(1) Revach OY (2) Cicerchia AM (3) Shorer O (4) Palin CA (5) Petrova B (6) Anderson S (7) Liu B (8) Park J (9) Chen L (10) Mehta A (11) Wright SJ (12) McNamee N (13) Tal-Mason A (14) Cattaneo G (15) Tiwari P (16) Xie H (17) Sweere JM (18) Cheng LC (19) Sigal N (20) Enrico E (21) Miljkovic M (22) Evans SA (23) Nguyen N (24) Whidden ME (25) Srinivasan R (26) Spitzer MH (27) Sun Y (28) Sharova T (29) Lawless AR (30) Michaud WA (31) Rasmussen MQ (32) Fang J (33) Brook JR (34) Chen F (35) Wang X (36) Ferrone CR (37) Lawrence DP (38) Sullivan RJ (39) Liu D (40) Sachdeva UM (41) Sen DR (42) Flaherty KT (43) Manguso RT (44) Bod L (45) Kellis M (46) Boland GM (47) Yizhak K (48) Yang J (49) Kanarek N (50) Sade-Feldman M (51) Hacohen N (52) Jenkins RW

Cell reports. Medicine

Revach et al. recently showed that in melanoma and other cancers, chronic TCR stimulation and type I IFN signaling in the tumor induced upregulation of CD38 (an ecto-enzyme involved in NAD+ catabolism) in CD8+ T cells in tumors. This drove a reduction in NAD+, leading to an impaired metabolic state and T cell dysfunction associated with resistance to ICB. Disrupting CD38 restored NAD+ pools and mitochondrial function, improved T cell function, and restored ICB sensitivity in melanoma organotypic tumor spheroids derived from patients with ICB-resistant melanoma.

ABSTRACT: CD38, an ecto-enzyme involved in NAD(+) catabolism, is highly expressed in exhausted CD8(+) T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38(+)CD8(+) T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD(+) pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD(+) as a vital metabolite to enhance those therapies.

Author Info: (1) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad In

Author Info: (1) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (3) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel. (4) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA; Medical University of Vienna, 1090 Vienna, Austria. (6) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (10) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (12) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (15) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (16) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (17) Teiko Bio, Salt Lake City, UT 84108, USA. (18) Teiko Bio, Salt Lake City, UT 84108, USA. (19) Teiko Bio, Salt Lake City, UT 84108, USA. (20) Teiko Bio, Salt Lake City, UT 84108, USA. (21) Teiko Bio, Salt Lake City, UT 84108, USA. (22) Teiko Bio, Salt Lake City, UT 84108, USA. (23) Teiko Bio, Salt Lake City, UT 84108, USA. (24) Teiko Bio, Salt Lake City, UT 84108, USA. (25) Teiko Bio, Salt Lake City, UT 84108, USA. (26) Teiko Bio, Salt Lake City, UT 84108, USA; Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (27) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (28) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (29) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (30) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (32) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (33) Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. (34) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (35) Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (36) Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (37) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (38) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (39) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (40) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (41) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (42) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (43) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (44) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (45) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (46) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (47) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel. (48) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (49) Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. (50) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (51) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (52) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: rjenkins@mgh.harvard.edu.

Citation: Cell Rep Med 2025 Jun 19 102210 Epub06/19/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40578364

Tags:

Different tumour-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies Spotlight 

(1) Damei I (2) Caidi A (3) Auclin E (4) Adam J (5) Mella S (6) Hasan M (7) Tartour E (8) Robert C (9) Corgnac S (10) Mami-Chouaib F

Nature communications | Free PMC Article

Using the MC38 tumor model, Damei et al. showed that CD103+CD8 TRM cells are involved in responses to anti-PD-1 treatment, but not CTLA-4 blockade. The benefits of anti-PD-1 treatment were compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. CTLA-4 blockade expanded CD49a+CD4+ TRM cells and increased tumor-specific CD4+ TIL-mediated cytotoxicity. CD49a+CD4+ TRM cells with cytotoxic potential were present in human melanoma and lung tumors. Furthermore, a high density of CD49a+CD4 TRM cells in pre-treatment melanoma was predictive of response to CTLA-4 plus PD-1 blockade therapy.

Contributed by Shishir Pant

(1) Damei I (2) Caidi A (3) Auclin E (4) Adam J (5) Mella S (6) Hasan M (7) Tartour E (8) Robert C (9) Corgnac S (10) Mami-Chouaib F

Nature communications | Free PMC Article

Using the MC38 tumor model, Damei et al. showed that CD103+CD8 TRM cells are involved in responses to anti-PD-1 treatment, but not CTLA-4 blockade. The benefits of anti-PD-1 treatment were compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. CTLA-4 blockade expanded CD49a+CD4+ TRM cells and increased tumor-specific CD4+ TIL-mediated cytotoxicity. CD49a+CD4+ TRM cells with cytotoxic potential were present in human melanoma and lung tumors. Furthermore, a high density of CD49a+CD4 TRM cells in pre-treatment melanoma was predictive of response to CTLA-4 plus PD-1 blockade therapy.

Contributed by Shishir Pant

ABSTRACT: The involvement of tumour-resident memory T (T(RM)) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103(+)CD8 T(RM) cells are involved in response to PD-1 blockade, CD49a(+)CD4 T(RM) cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a(+)CD4 T(RM) signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a(+)CD4 T(RM) cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a(+)CD4 T(RM) signature enriched in CTLA-4 and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a(+)CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a(+)CD4 T(RM) cells may correspond to a predictive biomarker of response to combined immunotherapy.

Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (2) INSE

Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (2) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (3) Department of Medicine, Institut Bergonié, Bordeaux, France. (4) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. Department of Pathology, Paris Saint Joseph Hospital, Paris, France. (5) Single Cell Biomarkers UTechS, Institut Pasteur, Universit Paris Cité, Paris, France. (6) Single Cell Biomarkers UTechS, Institut Pasteur, Université Paris Cité, Paris, France. (7) INSERM U970, Paris Cardiovascular Research Centre, Université Paris-Descartes, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris, France. (8) Dermatology Unit, Department of Oncology, Institut Gustave Roussy, Villejuif, France. (9) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. (10) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France. fathia.mami-chouaib@gustaveroussy.fr.

Citation: Nat Commun 2025 Jul 1 16:5588 Epub07/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40593647

Tags:

Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors

Spotlight 

(1) Sek K (2) Chen AXY (3) Cole T (4) Armitage JD (5) Tong J (6) Yap KM (7) Munoz I (8) Dunbar PA (9) Wu S (10) van Elsas MJ (11) Hidajat O (12) Scheffler C (13) Giuffrida L (14) Henderson MA (15) Meyran D (16) Souza-Fonseca-Guimaraes F (17) Nguyen D (18) Huang YK (19) de Menezes MN (20) Derrick EB (21) Chan CW (22) Todd KL (23) Chan JD (24) Li J (25) Lai J (26) Petley EV (27) Mardiana S (28) Bosco A (29) Waithman J (30) Parish IA (31) M¿lck C (32) Stewart GD (33) Kats L (34) House IG (35) Darcy PK (36) Beavis PA

Nature communications | Free PMC Article

Sek and Chen et al. demonstrated that overexpression of the adenosine receptor A1R in CAR T cells reduced cAMP levels, and enhanced baseline and antigen-induced cytokine production and effector differentiation. However, these cells exhibited early terminal differentiation in vivo, leading to reduced persistence and loss of the stem-like memory fraction. A CRISPR KI approach was used to restrict A1R expression to the tumor site via the NR4A2 promoter, which enhanced the efficacy of the CAR T cells against solid tumors. Gene network analysis identified the transcription factor IRF8 to play a major role downstream of A1R signaling.

Contributed by Morgan Janes

(1) Sek K (2) Chen AXY (3) Cole T (4) Armitage JD (5) Tong J (6) Yap KM (7) Munoz I (8) Dunbar PA (9) Wu S (10) van Elsas MJ (11) Hidajat O (12) Scheffler C (13) Giuffrida L (14) Henderson MA (15) Meyran D (16) Souza-Fonseca-Guimaraes F (17) Nguyen D (18) Huang YK (19) de Menezes MN (20) Derrick EB (21) Chan CW (22) Todd KL (23) Chan JD (24) Li J (25) Lai J (26) Petley EV (27) Mardiana S (28) Bosco A (29) Waithman J (30) Parish IA (31) M¿lck C (32) Stewart GD (33) Kats L (34) House IG (35) Darcy PK (36) Beavis PA

Nature communications | Free PMC Article

Sek and Chen et al. demonstrated that overexpression of the adenosine receptor A1R in CAR T cells reduced cAMP levels, and enhanced baseline and antigen-induced cytokine production and effector differentiation. However, these cells exhibited early terminal differentiation in vivo, leading to reduced persistence and loss of the stem-like memory fraction. A CRISPR KI approach was used to restrict A1R expression to the tumor site via the NR4A2 promoter, which enhanced the efficacy of the CAR T cells against solid tumors. Gene network analysis identified the transcription factor IRF8 to play a major role downstream of A1R signaling.

Contributed by Morgan Janes

ABSTRACT: The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A2A receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A1 receptor, a receptor that signals inversely to A2A receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A1 receptor overexpression significantly enhances Chimeric Antigen Receptor T cell effector function albeit at the expense of Chimeric Antigen Receptor T cell persistence. Through a CRISPR/Cas9 homology directed repair "knock-in" approach we demonstrate that Chimeric Antigen Receptor T cells engineered to express A1 receptor in a tumor-localized manner, enhances anti-tumor therapeutic efficacy. This is dependent on the transcription factor IRF8 and is transcriptionally unique when compared to A2A receptor deletion. This data provides a novel approach for enhancing Chimeric Antigen Receptor T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. kevin.sek@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbo

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. kevin.sek@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. kevin.sek@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (4) University of Western Australia, Perth, WA, Australia. Telethon Kids Institute, Perth, WA, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (16) Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (18) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (22) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (23) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (24) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (25) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (27) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (28) Asthma and Airway Disease Research Center, The University of Arizona, Tucson, AZ, USA. (29) University of Western Australia, Perth, WA, Australia. Telethon Kids Institute, Perth, WA, Australia. (30) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (31) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (32) Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. (33) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (34) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (35) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. phil.darcy@petermac.org. (36) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. paul.beavis@petermac.org.

Citation: Nat Commun 2025 Jul 3 16:6123 Epub07/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40610421

Tags:

Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis Spotlight 

(1) Liu R (2) Liu Q (3) Wang Y (4) Liu T (5) Zhang Z (6) Zhao C (7) Tao H (8) Ogando-Rivas E (9) Castillo P (10) Zhang W

Journal for immunotherapy of cancer | Free PMC Article

Focused on improving bacteria-mediated cancer immunotherapy responses in osteosarcoma (OS) with liver metastases, Liu, Liu, and Yang et al. engineered a novel Salmonella strain to express CCL2 and CCL9 (VNP-C-C). VNP-C-C accumulated within tumors and induced immunogenic cell death via the cGAS/STING pathway (leading to IFNα secretion), even in the absence of T cells. In immunocompetent mice, CCL2 and CCL9 further amplified anti-tumor responses by recruiting DCs, polarized M1-like macrophages and T cells into the TME, resulting in enhanced efficacy and survival in an immunocompetent OS lung metastasis model.

Contributed by Katherine Turner

(1) Liu R (2) Liu Q (3) Wang Y (4) Liu T (5) Zhang Z (6) Zhao C (7) Tao H (8) Ogando-Rivas E (9) Castillo P (10) Zhang W

Journal for immunotherapy of cancer | Free PMC Article

Focused on improving bacteria-mediated cancer immunotherapy responses in osteosarcoma (OS) with liver metastases, Liu, Liu, and Yang et al. engineered a novel Salmonella strain to express CCL2 and CCL9 (VNP-C-C). VNP-C-C accumulated within tumors and induced immunogenic cell death via the cGAS/STING pathway (leading to IFNα secretion), even in the absence of T cells. In immunocompetent mice, CCL2 and CCL9 further amplified anti-tumor responses by recruiting DCs, polarized M1-like macrophages and T cells into the TME, resulting in enhanced efficacy and survival in an immunocompetent OS lung metastasis model.

Contributed by Katherine Turner

BACKGROUND: Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of Salmonella typhimurium VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9. METHODS: VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (M_s)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis. RESULTS: VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, M_s, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models. CONCLUSION: The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.

Author Info: (1) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (2) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (3) Shanghai Chest Hospital of Shanghai Jiao Tong Universi

Author Info: (1) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (2) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (3) Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China. (4) Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. (5) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China. (6) Neurosurgery, University of Florida, Gainesville, Florida, USA. (7) Neurosurgery, University of Florida, Gainesville, Florida, USA. (8) Neurosurgery, University of Florida, Gainesville, Florida, USA. (9) Pediatrics, University of Florida, Gainesville, Florida, USA. (10) Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China zwb10368@rjh.com.cn.

Citation: J Immunother Cancer 2025 Jul 1 13: Epub07/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40592739

Tags:

IGM-7354, an immunocytokine with IL-15 fused to an anti-PD-L1 IgM, induces NK and CD8+ T cell-mediated cytotoxicity of PD-L1 positive tumor cells Spotlight 

(1) Desbois M (2) Giffon T (3) Yakkundi P (4) Denson CR (5) Sekar K (6) Hart KC (7) Santos D (8) Calhoun SE (9) Logronio K (10) Pandey S (11) Ng D (12) Saini AK (13) Wang BT (14) Keyt BA (15) Sinclair AM (16) Kotturi MF

Cancer immunology research

Desbois et al. generated IGM-7354, an IgM comprising ten PD-L1 binding sites which blocked PD-L1/PD-1 binding and a single IL15/IL15Rα complex which activated IL15Rβγ+ human NK and CD8+ T cells and rescued TEX cells in vitro. IGM-7354 delivered i.t. expanded human CD8+ T cells and reduced tumor growth in a humanized mouse breast cancer model, and boosted daratumumab (anti-CD38)-mediated ADCC in a multiple myeloma xenograft model and anti-CD19 CAR-T cell efficacy in a systemic lymphoma model even after tumor rechallenge. In monkeys, IgM-7354 increased NK and CD8+ T, particularly TEM cell proliferation, in blood, LN and BM.

Contributed by Paula Hochman

(1) Desbois M (2) Giffon T (3) Yakkundi P (4) Denson CR (5) Sekar K (6) Hart KC (7) Santos D (8) Calhoun SE (9) Logronio K (10) Pandey S (11) Ng D (12) Saini AK (13) Wang BT (14) Keyt BA (15) Sinclair AM (16) Kotturi MF

Cancer immunology research

Desbois et al. generated IGM-7354, an IgM comprising ten PD-L1 binding sites which blocked PD-L1/PD-1 binding and a single IL15/IL15Rα complex which activated IL15Rβγ+ human NK and CD8+ T cells and rescued TEX cells in vitro. IGM-7354 delivered i.t. expanded human CD8+ T cells and reduced tumor growth in a humanized mouse breast cancer model, and boosted daratumumab (anti-CD38)-mediated ADCC in a multiple myeloma xenograft model and anti-CD19 CAR-T cell efficacy in a systemic lymphoma model even after tumor rechallenge. In monkeys, IgM-7354 increased NK and CD8+ T, particularly TEM cell proliferation, in blood, LN and BM.

Contributed by Paula Hochman

ABSTRACT: IgM antibodies are preformed pentameric or hexameric molecules that can be engineered to generate high affinity and high avidity fully human antibody therapeutics. In this study, we report an immunocytokine, IGM-7354, which was designed to bind multiple PD-L1 receptors while trans-presenting a single IL-15/IL-15R_ complex on the joining chain to IL-15R__-expressing cytotoxic natural killer (NK) and CD8+ T-cells. We evaluated the pharmacological and anti-tumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T-cells, both in vitro using healthy human PBMCs and in vivo in humanized mice, through the IL-15/IL-15R_ complex. In a mixed-lymphocyte reaction assay with exhausted human T-cells, IGM-7354 restored the secretion of IFN_ compared to the IL-15/IL-15R_ complex or anti-PD-L1 alone, suggesting a rescue of exhausted T-cells in vitro. Robust single agent activity was observed in the humanized PD-L1+ MDA-MB-231 breast cancer mouse model. Anti-tumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 CAR T-cell therapies in Raji lymphoma models. Finally, in cynomolgus monkeys, pharmacodynamic activity of increased NK and CD8+ T-cell proliferation was observed in multiple tissue compartments. Taken together, this study demonstrates the feasibility of developing a safe and effective IgM-based immunocytokine for the treatment of cancer, exploiting the multivalency of an IgM antibody to bind PD-L1 with high affinity and avidity and stimulate NK and CD8+ T-cell effectors.

Author Info: (1) IGM Biosciences (United States), Mountain View, United States. (2) IGM Biosciences (United States), Mountain View, United States. (3) IGM Biosciences (United States), Mountain

Author Info: (1) IGM Biosciences (United States), Mountain View, United States. (2) IGM Biosciences (United States), Mountain View, United States. (3) IGM Biosciences (United States), Mountain View, United States. (4) IGM Biosciences (United States), Mountain View, United States. (5) IGM Biosciences (United States), Mountain View, United States. (6) IGM Biosciences (United States), Mountain View, United States. (7) IGM Biosciences (United States), Mountain View, United States. (8) IGM Biosciences Inc, Mountain View, CA, United States. (9) Compugen USA, South San Francisco, CA, United States. (10) IGM Biosciences (United States), Mountain View, United States. (11) IGM Biosciences (United States), Mountain View, United States. (12) IGM Biosciences (United States), Mountain View, CA, United States. (13) IGM Biosciences Inc, Mountain View, CA, United States. (14) IGM Biosciences (United States), Mountain View, CA, United States. (15) IGM Biosciences (United States), Mountain View, CA, United States. (16) IGM Biosciences (United States), Mountain View, CA, United States.

Citation: Cancer Immunol Res 2025 May 22 Epub05/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40402523

Tags:

Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny Spotlight 

(1) Nowicki TS (2) Deen NNA (3) Peters CW (4) Comin-Anduix B (5) Medina E (6) Puig-Saus C (7) Carretero IB (8) Kaplan-Lefko P (9) Macabali MH (10) Garcilazo IP (11) Chen D (12) Pang J (13) Berent-Maoz B (14) Haile S (15) Rodriguez J (16) Kawakami M (17) Kidd CK (18) Champhekar A (19) Carlucci G (20) Vega-Crespo A (21) Chmielowski B (22) Singh A (23) Federman N (24) Schiller GM (25) Larson SJ (26) Allen-Auerbach M (27) Klomhaus AM (28) Zack J (29) Baltimore D (30) Yang L (31) Kohn DB (32) Witte ON (33) Ribas A

Nature communications | Free PMC Article

To overcome the poor persistence and progressive loss of functionality of TCR-engineered T cells, in vivo, Nowicki et al. evaluated tandem treatment with autologous blood-derived T cells and hematopoietic stem cells (HSCs), both engineered with an NY-ESO-TCR. The HSCs also contained the suicide/reporter gene sr39TK to allow for in vivo visualization. In a first-in-human clinical trial in patients with solid tumors, treatment was both safe and feasible (despite clinical difficulties), with early evidence of tumor regression. In circulation, T cell progeny derived from HSCs expressed the engineered TCRs and showed antigen-specific functionality. In vivo imaging aligned with peripheral blood samples.

Contributed by Lauren Hitchings

(1) Nowicki TS (2) Deen NNA (3) Peters CW (4) Comin-Anduix B (5) Medina E (6) Puig-Saus C (7) Carretero IB (8) Kaplan-Lefko P (9) Macabali MH (10) Garcilazo IP (11) Chen D (12) Pang J (13) Berent-Maoz B (14) Haile S (15) Rodriguez J (16) Kawakami M (17) Kidd CK (18) Champhekar A (19) Carlucci G (20) Vega-Crespo A (21) Chmielowski B (22) Singh A (23) Federman N (24) Schiller GM (25) Larson SJ (26) Allen-Auerbach M (27) Klomhaus AM (28) Zack J (29) Baltimore D (30) Yang L (31) Kohn DB (32) Witte ON (33) Ribas A

Nature communications | Free PMC Article

To overcome the poor persistence and progressive loss of functionality of TCR-engineered T cells, in vivo, Nowicki et al. evaluated tandem treatment with autologous blood-derived T cells and hematopoietic stem cells (HSCs), both engineered with an NY-ESO-TCR. The HSCs also contained the suicide/reporter gene sr39TK to allow for in vivo visualization. In a first-in-human clinical trial in patients with solid tumors, treatment was both safe and feasible (despite clinical difficulties), with early evidence of tumor regression. In circulation, T cell progeny derived from HSCs expressed the engineered TCRs and showed antigen-specific functionality. In vivo imaging aligned with peripheral blood samples.

Contributed by Lauren Hitchings

ABSTRACT: Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861.

Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbi

Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. (2) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (3) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (4) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. (5) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (6) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (7) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (8) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (9) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (10) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (11) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (12) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (13) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (14) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (15) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (16) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (17) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (18) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (20) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (21) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (22) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (23) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, CA, USA. (24) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (25) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (26) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (27) Department of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (28) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (29) Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. (30) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. (31) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. (32) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (33) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.

Citation: Nat Commun 2025 Jul 1 16:5599 Epub07/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40593578

Tags:

FcγRIIIa is a noncanonical costimulatory molecule for CD8 T cells

Spotlight 

(1) Kao KS (2) Pihlstrom NL (3) Niejadlik EG (4) Cantaert T (5) Ahmed R (6) Ravetch JV (7) Bournazos S

Proceedings of the National Academy of Sciences of the United States of America

Kao et al. showed that at steady state, primary human T cells and T cells from FcγR-humanized mouse strains lacked FcγR expression, except for a small fraction of CD8+ T cells that expressed FcγRIIIa. In cohorts of COVID-19 and dengue patients and in FcγR-humanized mouse virus infection models, FcγRIIIa+CD8+ T cells increased in frequency, tracking with disease severity and immune response dynamics, and were phenotypically short-lived terminal effector CD8+ T cells with low canonical costimulatory molecule expression. FcγRIIIa crosslinking by IgG immune complexes alone did not activate, but rather synergized with TCR signaling to costimulate FcγRIIIa+CD8+ T cell activation.

Contributed by Paula Hochman

(1) Kao KS (2) Pihlstrom NL (3) Niejadlik EG (4) Cantaert T (5) Ahmed R (6) Ravetch JV (7) Bournazos S

Proceedings of the National Academy of Sciences of the United States of America

Kao et al. showed that at steady state, primary human T cells and T cells from FcγR-humanized mouse strains lacked FcγR expression, except for a small fraction of CD8+ T cells that expressed FcγRIIIa. In cohorts of COVID-19 and dengue patients and in FcγR-humanized mouse virus infection models, FcγRIIIa+CD8+ T cells increased in frequency, tracking with disease severity and immune response dynamics, and were phenotypically short-lived terminal effector CD8+ T cells with low canonical costimulatory molecule expression. FcγRIIIa crosslinking by IgG immune complexes alone did not activate, but rather synergized with TCR signaling to costimulate FcγRIIIa+CD8+ T cell activation.

Contributed by Paula Hochman

ABSTRACT: A critical component of the function of IgG antibodies is their capacity to engage specialized cellular receptors, Fcγ receptors (FcγRs), expressed on effector leukocytes. Highlighting the importance of FcγR-mediated signaling in the regulation of the fate, activation, and differentiation status of leukocytes, FcγRs are ubiquitously expressed by nearly all leukocyte populations. Here, we report that while at steady state, T cells are negative for all classes of FcγRs, CD8 T cells specifically induce the expression of the activating FcγR, FcγRIIIa, in response to viral infection in cohorts of COVID-19 and dengue patients, as well as in virus infection models using FcγR humanized mouse strains. In in vivo mechanistic studies, we demonstrate that induction of FcγRIIIa expression on effector CD8 T cells follows a well-defined trajectory that closely tracks the course and magnitude of the immune response, while immune resolution is characterized by receptor downregulation. Uniquely to these CD8 T cells, FcγRIIIa crosslinking alone is paradoxically insufficient to elicit T cell activation and cytotoxicity. However, when coupled with T cell receptor (TCR) stimulation, it results in synergistic cellular activation and, compensates for the downregulation of canonical costimulatory molecules on terminal effector CD8 T cells. These results reveal a previously unappreciated role for FcγRIIIa as a unique costimulatory molecule that synergizes with TCR signaling to lower the effective threshold required for CD8 T cell activation, highlighting the role of virally induced antibodies in modulating CD8 effector cell responses.

Author Info: (1) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (2) Laboratory of Molecular Genetics and Immunology, The Rockefeller University

Author Info: (1) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (2) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (3) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (4) Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh 120210, Cambodia. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Winship Cancer Institute of Emory University, Atlanta, GA 30322. (6) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (7) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.

Citation: Proc Natl Acad Sci U S A 2025 Jul 8 122:e2509016122 Epub07/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40591599

Tags:

The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells

Spotlight 

(1) Humblin E (2) Korpas I (3) Prokhnevska N (4) Vaidya A (5) Filipescu D (6) Lu J (7) van der Heide V (8) de Carvalho Fraga CA (9) Bobrowski T (10) Marks A (11) Park MD (12) Nakaya HI (13) Bernstein E (14) Brown BD (15) Lujambio A (16) Dominguez-Sola D (17) Rosenberg BR (18) Kamphorst AO

Immunity

Humblin et al. showed that sustained ICOS signaling impaired CD8+ T cell survival and function during chronic antigen exposure. ICOS was expressed on the surface of TCF-1+ Tpex cells, and genetic ablation of ICOS led to enrichment of FoxO1 target genes and memory-like features of Tpex cells. ICOS deficiency promoted virus-specific effector-like Tex cell differentiation, survival, and functionality in chronic LCMV infection in a FoxO1-dependent manner. ICOSL blockade expanded virus- and tumor-specific effector-like PD-1+CD8+ T cells, reduced viral load and tumor growth, and potentiated PD-1 targeted immunotherapy.

Contributed by Shishir Pant

(1) Humblin E (2) Korpas I (3) Prokhnevska N (4) Vaidya A (5) Filipescu D (6) Lu J (7) van der Heide V (8) de Carvalho Fraga CA (9) Bobrowski T (10) Marks A (11) Park MD (12) Nakaya HI (13) Bernstein E (14) Brown BD (15) Lujambio A (16) Dominguez-Sola D (17) Rosenberg BR (18) Kamphorst AO

Immunity

Humblin et al. showed that sustained ICOS signaling impaired CD8+ T cell survival and function during chronic antigen exposure. ICOS was expressed on the surface of TCF-1+ Tpex cells, and genetic ablation of ICOS led to enrichment of FoxO1 target genes and memory-like features of Tpex cells. ICOS deficiency promoted virus-specific effector-like Tex cell differentiation, survival, and functionality in chronic LCMV infection in a FoxO1-dependent manner. ICOSL blockade expanded virus- and tumor-specific effector-like PD-1+CD8+ T cells, reduced viral load and tumor growth, and potentiated PD-1 targeted immunotherapy.

Contributed by Shishir Pant

ABSTRACT: During persistent antigen stimulation, CD8(+) T cell responses are maintained by progenitor exhausted CD8(+) T (Tpex) cells. Tpex cells respond to blockade of the inhibitory receptor programmed cell death-1 (PD-1), and regulation of their differentiation is critical for immunotherapies. Tpex cells highly express inducible costimulator (ICOS), but how ICOS modulates PD-1(+)CD8(+) T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8(+) T cells. Loss of ICOS potentiated activity of the transcription factor forkhead box O1 (FoxO1) and memory-like features of Tpex cells. ICOS-deficient Tpex cells were poised to generate effecor-like cells with improved survival and cytokine production. ICOS-ligand (ICOSL) blockade expanded effector-like PD-1(+)CD8(+) T cells, reduced viral load, and improved response to PD-1 blockade. Similarly, in a mouse model of hepatocellular carcinoma, ICOS inhibition enhanced tumor-specific CD8(+) T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8(+) T cell responses during chronic antigen exposure.

Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS

Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. Electronic address: etienne.humblin@gmail.com. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (5) Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (6) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (8) Federal University of Alagoas, Arapiraca Campus, Center of Medical Sciences, Bom Sucesso, Alagoas 57309, Brazil. (9) Department of Microbiology, ISMMS, New York, NY 10029, USA. (10) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, ISMMS, New York, NY 10029, USA. (11) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA. (12) Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of S‹o Paulo, S‹o Paulo 05508, Brazil; Hospital Israelita Albert Einstein, S‹o Paulo 05620, Brazil. (13) Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Icahn Genomics Institute, ISMMS, New York, NY 10029, USA. (15) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. (16) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA; Department of Pathology, ISMMS, New York, NY 10029, USA. (17) Department of Microbiology, ISMMS, New York, NY 10029, USA. (18) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, ISMMS, New York, NY 10029, USA; Tisch Cancer Institute, ISMMS, New York, NY 10029, USA; Department of Oncological Sciences, ISMMS, New York, NY 10029, USA. Electronic address: alice.kamphorst@mssm.edu.

Citation: Immunity 2025 Jul 1 Epub07/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40628269

Tags:

CTG-initiated cryptic peptide translation up and downstream of a canonical ATG start codon is enhanced by TLR stimulation and induces tumor regression in mice Spotlight 

(1) Song Z (2) Lim Y (3) van Krimpen A (4) Geleijnse MAA (5) Messchendorp M (6) Voerman JSA (7) Li L (8) Tondeur EGM (9) Mishra G (10) Hos BJ (11) Grashof DGB (12) Stadhouders R (13) van de Werken HJG (14) Katsikis PD (15) Schliehe C

Cancer immunology research

Song et al used stop codon-separated tandem constructs encoding a control peptide via canonical ATG and SIINFEKL via noncanonical CTG to examine noncanonical translation. TLR stimulation selectively enhanced translation of CTG-SIINFEKL (and genome wide noncanonical-ORF) in BMDCs, and stronger OTI T cell priming was observed when CTG peptide was upstream of a canonical ORF. OTI T cells efficiently killed cancer cells expressing very low levels of CTG-SIINFEKL, where MHCI expression was the limiting factor. In vivo, tumors expressing the construct could be controlled by OTI T cells, but efficacy varied by context.

Contributed by Morgan Janes

(1) Song Z (2) Lim Y (3) van Krimpen A (4) Geleijnse MAA (5) Messchendorp M (6) Voerman JSA (7) Li L (8) Tondeur EGM (9) Mishra G (10) Hos BJ (11) Grashof DGB (12) Stadhouders R (13) van de Werken HJG (14) Katsikis PD (15) Schliehe C

Cancer immunology research

Song et al used stop codon-separated tandem constructs encoding a control peptide via canonical ATG and SIINFEKL via noncanonical CTG to examine noncanonical translation. TLR stimulation selectively enhanced translation of CTG-SIINFEKL (and genome wide noncanonical-ORF) in BMDCs, and stronger OTI T cell priming was observed when CTG peptide was upstream of a canonical ORF. OTI T cells efficiently killed cancer cells expressing very low levels of CTG-SIINFEKL, where MHCI expression was the limiting factor. In vivo, tumors expressing the construct could be controlled by OTI T cells, but efficacy varied by context.

Contributed by Morgan Janes

ABSTRACT: Cytotoxic T-lymphocytes (CTLs) screen cells for signs of infection and transformation by recognizing peptides displayed on major histocompatibility complex (MHC) class I molecules. Next to canonical ATG-initiated open reading frames (ORFs), non-canonical translation can result in synthesis of non-conventional or `cryptic« polypeptides. These can originate from translation initiation at non-canonical start codons, a process previously associated with inflammation and oncogenic transformation. Cryptic translation products are efficiently presented on MHC class I molecules and therefore increasingly recognized as potential targets for cancer immunotherapy. Here, we studied how localization of a CTG-initiated ORF relative to a canonical ATG start codon can influence cryptic expression after innate immune stimulation. We generated immortalized C57BL/6J mouse-derived bone marrow progenitor cells (HoxB8) expressing tandem minigene constructs, which encoded a CTG-driven chicken ovalbumin-derived SIINFEKL (S8L) epitope (CTG-S8L; H-2Kb-restriced) either up or downstream of a canonical ATG-initiated UTY-derived peptide WI9 (ATG-WI9; H-2Db-restriced). Treatment of HoxB8-derived macrophages with Toll-like receptor agonists enhanced position-independent CTG-S8L translation, without affecting ATG-driven expression. Downstream CTG-S8L translation was driven by leaky scanning or ribosome re-initiation rather than read-through translation. Mouse AE17 mesothelioma and B16F10 melanoma cells expressing cryptic S8L either up or downstream of a canonical ORF were efficiently killed by H-2Kb/S8L-restriced OT-I T-cells in vitro, even though their antigen expression levels were extremely low. Mice implanted with tumors expressing cryptic S8L showed delayed tumor progression in vivo. In summary, our study contributes to the characterization of non-canonical start codon-driven cryptic antigen translation and highlights its potential for cancer immunotherapy.

Author Info: (1) Erasmus MC, Netherlands. (2) Erasmus MC, Rotterdam, ZH, Netherlands. (3) Erasmus MC Rotterdam, Rotterdam, Netherlands. (4) Erasmus MC, Netherlands. (5) Erasmus MC, Netherlands.

Author Info: (1) Erasmus MC, Netherlands. (2) Erasmus MC, Rotterdam, ZH, Netherlands. (3) Erasmus MC Rotterdam, Rotterdam, Netherlands. (4) Erasmus MC, Netherlands. (5) Erasmus MC, Netherlands. (6) Erasmus MC, Netherlands. (7) Erasmus MC, Rotterdam, Netherlands. (8) Erasmus MC, Netherlands. (9) Erasmus MC, Netherlands. (10) Erasmus MC, Netherlands. (11) Erasmus MC, Rotterdam, Netherlands. (12) Erasmus MC, Rotterdam, Netherlands. (13) Erasmus MC Cancer Institute, Rotterdam, Netherlands. (14) Erasmus MC, Rotterdam, Netherlands. (15) Erasmus MC, Rotterdam, Netherlands.

Citation: Cancer Immunol Res 2025 Jun 3 Epub06/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40459529

Tags:
Close Modal

Subscribe to our mailing list

GDPR Marketing Permissions

The Fritsch Foundation/ACIR.org will use the information you provide on this form to be in touch with you and to send you a weekly digest on cance immunotherapy. Click below to confirm that you want to receive the weekly digest by:

You can change your mind at any time by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at contact@acir.org. We will treat your information with respect and will never share it with any third-parties. By clicking below, you agree that we may process your information in accordance with these terms.

We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices here.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.