High levels of endogenous Omega-3 Fatty Acids promote dendritic-cell antigen presentation and improve dendritic cell-based cancer vaccine efficacy in mice
(1) Tiwary S (2) Hsu KS (3) Goldfarbmuren KC (4) Xia Z (5) Berzofsky JA
EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer
(1) Arai K (2) Nishito Y (3) Mizuno H (4) Motoi N (5) Hiraoka N (6) Fuse M (7) Arai Y (8) Shibata T (9) Sonobe Y (10) Kayukawa Y (11) Maruyama T (12) Fukuda H (13) Mizoguchi Y (14) Aikawa Y (15) Yoshida Y (16) Watanabe SI (17) Sakamoto H (18) Yamashita M (19) Kitano S (20) Nagata Y (21) Mitsumori R (22) Ozaki K (23) Niida S (24) Kanai Y (25) Hirayama A (26) Soga T (27) Yoshida T (28) Yasuda K (29) Ochiai A (30) Tsunoda H (31) Aoki K
(1) Arai K (2) Nishito Y (3) Mizuno H (4) Motoi N (5) Hiraoka N (6) Fuse M (7) Arai Y (8) Shibata T (9) Sonobe Y (10) Kayukawa Y (11) Maruyama T (12) Fukuda H (13) Mizoguchi Y (14) Aikawa Y (15) Yoshida Y (16) Watanabe SI (17) Sakamoto H (18) Yamashita M (19) Kitano S (20) Nagata Y (21) Mitsumori R (22) Ozaki K (23) Niida S (24) Kanai Y (25) Hirayama A (26) Soga T (27) Yoshida T (28) Yasuda K (29) Ochiai A (30) Tsunoda H (31) Aoki K
Author Info: (1) National Cancer Center Research Institute, Tokyo, Japan. (2) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (3) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa
Author Info: (1) National Cancer Center Research Institute, Tokyo, Japan. (2) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (3) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (4) National Cancer Center Research Institute, Tokyo, Japan. (5) National Cancer Center Research Institute, Tokyo, Japan. (6) National Cancer Center Research Institute, Tokyo, Japan. (7) National Cancer Center Research Institute, Tokyo, Tokyo, Japan. (8) National Cancer Center Research Institute, Tokyo, Japan. (9) Chugai Pharmaceutical Co., Ltd., Yokohama City, Japan. (10) Chugai Pharmaceutical Co. Ltd., Yokohama, Kanagawa, Japan. (11) Roche (Switzerland), Basel, Basel-stadt, Switzerland. (12) Tokyo Women's Medical University, Tokyo, Japan. (13) Japanese Foundation For Cancer Research, Koto-ku, Tokyo, Japan. (14) National Cancer Center Research Institute, Tokyo, Tokyo, Japan. (15) National Cancer Center Hospital East, Chuo-ku, Tokyo, Japan. (16) National Cancer Center Hospital East, Tokyo, Japan. (17) National Cancer Center Research Institute, Tokyo, Chuo-ku, Japan. (18) The Cancer Institute Hospital of JFCR, Koto-ku, Tokyo, Japan. (19) Japanese Foundation For Cancer Research, Koto-ku, Tokyo, Japan. (20) Tokyo Medical and Dental University, Tokyo, Japan. (21) National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. (22) National Center for Geriatrics and Gerontology, Obu, Japan. (23) National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. (24) Keio University, Tokyo, Japan. (25) Keio University, Tsuruoka, Yamagata, Japan. (26) Keio University, Tsuruoka, Yamagata, Japan. (27) National Cancer Center Hospital East, Chuo-ku, Tokyo, Japan. (28) National Center for Global Health and Medicine, Japan. (29) Tokyo University of Science, Noda, Chiba, Japan. (30) Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. (31) National Cancer Center Research Institute, Tokyo, Tokyo, Japan.
Citation: Cancer Immunol Res 2025 Jul 8 Epub07/08/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40627846
Humoral determinants of checkpoint immunotherapy
(1) Dai Y (2) Aizenbud L (3) Qin K (4) Austin M (5) Jaycox JR (6) Cunningham J (7) Wang EY (8) Zhang L (9) Fischer S (10) Carroll SM (11) van Aggelen H (12) Kluger Y (13) Herold KC (14) Furchtgott L (15) Kluger HM (16) Ring AM
Dai, Aizenbud, and Qin et al. profiled the reactivities of autoantibodies (AAbs) from healthy donors and ICB-treated patients. AAb reactivities were diverse and often rare, differed between patients and healthy donors, generally did not associate with irAEs, and were largely unaffected by ICB. AAbs against inhibitory molecules, inflammatory cytokines, and surface TAAs associated with ICB response, while AAbs against costimulatory molecules or BMP receptors associated with non-responders. Functional inhibition by AAbs was validated in vitro, and blockade of AAb targets associated with responders (e.g., IFN-I and TL1A) supported ICB efficacy in mouse models.
Contributed by Alex Najibi
(1) Dai Y (2) Aizenbud L (3) Qin K (4) Austin M (5) Jaycox JR (6) Cunningham J (7) Wang EY (8) Zhang L (9) Fischer S (10) Carroll SM (11) van Aggelen H (12) Kluger Y (13) Herold KC (14) Furchtgott L (15) Kluger HM (16) Ring AM
Dai, Aizenbud, and Qin et al. profiled the reactivities of autoantibodies (AAbs) from healthy donors and ICB-treated patients. AAb reactivities were diverse and often rare, differed between patients and healthy donors, generally did not associate with irAEs, and were largely unaffected by ICB. AAbs against inhibitory molecules, inflammatory cytokines, and surface TAAs associated with ICB response, while AAbs against costimulatory molecules or BMP receptors associated with non-responders. Functional inhibition by AAbs was validated in vitro, and blockade of AAb targets associated with responders (e.g., IFN-I and TL1A) supported ICB efficacy in mouse models.
Contributed by Alex Najibi
ABSTRACT: Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established(1,2), the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling(3) to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the 'exoproteome'). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.
Author Info: (1) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (2) Yale Cancer Center, New Haven, CT, USA. (3) Division of Translational Science and Therapeutics, Fr
Author Info: (1) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (2) Yale Cancer Center, New Haven, CT, USA. (3) Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (4) Yale Cancer Center, New Haven, CT, USA. (5) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (6) Program of Applied Mathematics, Yale University, New Haven, CT, USA. (7) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (8) Yale Cancer Center, New Haven, CT, USA. (9) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. (10) Seranova Bio, South San Francisco, CA, USA. (11) Seranova Bio, South San Francisco, CA, USA. (12) Program of Applied Mathematics, Yale University, New Haven, CT, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. (13) Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (14) Seranova Bio, South San Francisco, CA, USA. leon@seranovabio.com. (15) Yale Cancer Center, New Haven, CT, USA. harriet.kluger@yale.edu. (16) Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. aaronring@fredhutch.org.
Citation: Nature 2025 Jul 23 Epub07/23/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40702172
Lymph-node-derived stem-like but not tumor-tissue-resident CD8+ T cells fuel anticancer immunity
(1) Wijesinghe SKM (2) Rausch L (3) Gabriel SS (4) Galletti G (5) De Luca M (6) Qin L (7) Wen L (8) Tsui C (9) Man K (10) Heyden L (11) Mason T (12) Newland LD (13) Kueh A (14) Liao Y (15) Chisanga D (16) Swatler J (17) Voulaz E (18) Marulli G (19) Errico V (20) Losurdo A (21) Rossi GR (22) Souza-Fonseca-Guimaraes F (23) Huntington ND (24) Gebhardt T (25) Utzschneider DT (26) Herold MJ (27) Shi W (28) Schroeder J (29) Lugli E (30) Kallies A
Wijesinghe, Rausch, et al. studied various T cell subsets in genetic murine tumor models. Intratumor tissue resident-like CD8+ T cells were found not to be required for tumor control or ICB efficacy and could not differentiate into effector cells due to TGFβ exposure. In the tumor-draining lymph nodes, a population of precursors of exhausted CD8+ T cells was detected that was MYB-dependent. This population was essential for antitumor responses, had stem-like properties, and generated CX3CR1+ effector cells that migrated to tumors in response to ICB.
(1) Wijesinghe SKM (2) Rausch L (3) Gabriel SS (4) Galletti G (5) De Luca M (6) Qin L (7) Wen L (8) Tsui C (9) Man K (10) Heyden L (11) Mason T (12) Newland LD (13) Kueh A (14) Liao Y (15) Chisanga D (16) Swatler J (17) Voulaz E (18) Marulli G (19) Errico V (20) Losurdo A (21) Rossi GR (22) Souza-Fonseca-Guimaraes F (23) Huntington ND (24) Gebhardt T (25) Utzschneider DT (26) Herold MJ (27) Shi W (28) Schroeder J (29) Lugli E (30) Kallies A
Wijesinghe, Rausch, et al. studied various T cell subsets in genetic murine tumor models. Intratumor tissue resident-like CD8+ T cells were found not to be required for tumor control or ICB efficacy and could not differentiate into effector cells due to TGFβ exposure. In the tumor-draining lymph nodes, a population of precursors of exhausted CD8+ T cells was detected that was MYB-dependent. This population was essential for antitumor responses, had stem-like properties, and generated CX3CR1+ effector cells that migrated to tumors in response to ICB.
ABSTRACT: CD8(+) T cell-mediated tumor control and efficacy of immune checkpoint blockade (ICB) are associated with both precursors of exhausted T (T(PEX)) cells and tissue-resident memory T cells. Their relationships and relative contribution to tumor control, however, are insufficiently understood. Using single-cell RNA sequencing and genetic mouse models, we systematically dissected the heterogeneity and function of cytotoxic T cells in tumors and tumor-draining lymph nodes (tdLNs). We found that intratumoral TCF1(+) T(PEX) cells and their progeny acquired a tissue-residency program that limits their contribution to tumor control and ICB response. By contrast, MYB-dependent stem-like T(PEX) cells residing in tdLNs sustained CD8(+) T cell infiltration into tumors and mediated ICB response. The cytokine TGF_ was the central factor that enforced residency of intratumoral CD8(+) T cells and limited the abundance of stem-like T(PEX) cells in tdLNs, thereby restraining tumor control. A similar network of TGF_-constrained intratumoral and extratumoral CD8(+) T cells with precursor and residency characteristics was found in human cancer.
Author Info: (1) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (2) Department of
Author Info: (1) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (2) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (3) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (4) IRCCS Humanitas Research Hospital, Rozzano, Italy. School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA. (5) IRCCS Humanitas Research Hospital, Rozzano, Italy. (6) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (7) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (8) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (9) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (10) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (11) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (12) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. Institute of Experimental Oncology (IEO), Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany. (13) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (14) Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. (15) Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. (16) IRCCS Humanitas Research Hospital, Rozzano, Italy. (17) IRCCS Humanitas Research Hospital, Rozzano, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. (18) IRCCS Humanitas Research Hospital, Rozzano, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. (19) IRCCS Humanitas Research Hospital, Rozzano, Italy. (20) IRCCS Humanitas Research Hospital, Rozzano, Italy. (21) Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia. (22) Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia. (23) Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. oNKo-Innate, Melbourne, Victoria, Australia. (24) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (25) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (26) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (27) Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. (28) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. (29) IRCCS Humanitas Research Hospital, Rozzano, Italy. (30) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. axel.kallies@unimelb.edu.au. Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn, Bonn, Germany. axel.kallies@unimelb.edu.au.
Citation: Nat Immunol 2025 Aug 26:1367-1383 Epub07/29/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40730900
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The tumor-sentinel lymph node immunomigratome reveals CCR7⁺ dendritic cells drive response to sequenced immunoradiotherapy
(1) Saddawi-Konefka R (2) Msari RA (3) Tang S (4) Philips C (5) Sadat S (6) Clubb LM (7) Luna S (8) Fassardi S (9) Jones R (10) Pietryga IF (11) Faraji F (12) Schokrpur S (13) Yung BS (14) Allevato MM (15) Decker KE (16) Nasamran CA (17) Chilin-Fuentes D (18) Rosenthal SB (19) Jensen SM (20) Fox BA (21) Bell RB (22) Gutkind JS (23) Sharabi A (24) Califano JA
Using orthotopic 4MOSC murine models, Saddawi-Konefka et al. showed that the preferential migration of immune cells to the tumor-draining sentinel lymph nodes (SLNs) creates a unique immunologic niche with distinct cellular composition and transcriptional profiles. Sequencing tumor-directed lymphatic-sparing immunomodulatory radiation therapy prior to anti-PD-1 therapy enhanced local immunosurveillance, antigen presentation, and the efficacy of anti-PD-1 therapy, leading to a high rate of durable cures. MMP9-dependent entry of CCR7+ dendritic cells into the SLN was critical for the efficacy of tumor-directed immunoradiotherapy.
Contributed by Shishir Pant
(1) Saddawi-Konefka R (2) Msari RA (3) Tang S (4) Philips C (5) Sadat S (6) Clubb LM (7) Luna S (8) Fassardi S (9) Jones R (10) Pietryga IF (11) Faraji F (12) Schokrpur S (13) Yung BS (14) Allevato MM (15) Decker KE (16) Nasamran CA (17) Chilin-Fuentes D (18) Rosenthal SB (19) Jensen SM (20) Fox BA (21) Bell RB (22) Gutkind JS (23) Sharabi A (24) Califano JA
Using orthotopic 4MOSC murine models, Saddawi-Konefka et al. showed that the preferential migration of immune cells to the tumor-draining sentinel lymph nodes (SLNs) creates a unique immunologic niche with distinct cellular composition and transcriptional profiles. Sequencing tumor-directed lymphatic-sparing immunomodulatory radiation therapy prior to anti-PD-1 therapy enhanced local immunosurveillance, antigen presentation, and the efficacy of anti-PD-1 therapy, leading to a high rate of durable cures. MMP9-dependent entry of CCR7+ dendritic cells into the SLN was critical for the efficacy of tumor-directed immunoradiotherapy.
Contributed by Shishir Pant
ABSTRACT: Surgical ablation or broad radiation of tumor-draining lymph nodes can eliminate the primary tumor response to immunotherapy, highlighting the crucial role of these nodes in mediating the primary tumor response. Here, we show that immunoradiotherapy efficacy is dependent on treatment sequence and migration of modulated dendritic cells from tumor to sentinel lymph nodes. Using a tamoxifen-inducible reporter paired with CITE-sequencing in a murine model of oral cancer, we comprehensively characterize tumor immune cellular migration through lymphatic channels to sentinel lymph nodes at single-cell resolution, revealing a unique immunologic niche defined by distinct cellular phenotypic and transcriptional profiles. Through a structured approach of sequential immunomodulatory radiotherapy and checkpoint inhibition, we show that sequenced, lymphatic-sparing, tumor-directed radiotherapy followed by PD-1 inhibition achieves complete and durable tumor responses. Mechanistically, this treatment approach enhances migration of activated CCR7+ dendritic cell surveillance across the tumor-sentinel lymph node axis, revealing a shift from their canonical role in promoting tolerance to driving antitumor immunity. Overall, this work supports rationally sequencing immune-sensitizing, lymphatic-preserving, tumor-directed radiotherapy followed by immune checkpoint inhibition to optimize tumor response to immunoradiotherapy by driving activated dendritic cells to draining sentinel lymph nodes.
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. rsaddawi@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla,
Author Info: (1) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. rsaddawi@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla, CA, USA. rsaddawi@health.ucsd.edu. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. rsaddawi@health.ucsd.edu. (2) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (3) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (4) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (5) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (6) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (7) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (8) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (9) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (10) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (11) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (12) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Medicine, Division of Hematology-Oncology, UC Davis, Sacramento, CA, USA. (13) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (14) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (15) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. (16) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (17) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (18) Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. (19) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (20) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (21) Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, OR, USA. (22) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Pharmacology, UC San Diego, La Jolla, CA, USA. (23) Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, UC San Diego School of Medicine, San Diego, CA, USA. (24) Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. jcalifano@health.ucsd.edu. Moores Cancer Center, UC San Diego, La Jolla, CA, USA. jcalifano@health.ucsd.edu. Gleiberman Head and Neck Cancer Center, Moores Cancer Center, UC San Diego, La Jolla, CA, USA. jcalifano@health.ucsd.edu.
Citation: Nat Commun 2025 Jul 17 16:6578 Epub07/17/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40675962
PD-1 is requisite for skin TRM cell formation and specification by TGFβ
(1) Devi KSP (2) Wang E (3) Jaiswal A (4) Konieczny P (5) Kim TG (6) Nirschl CJ (7) Verma A (8) Liu Y (9) Milczanowski J (10) Christo SN (11) Gandolfo LC (12) Haitz K (13) Vardam TD (14) Wu P (15) King SL (16) Tse SW (17) Pradhan K (18) Jiang X (19) Tian T (20) Fuhlbrigge RC (21) Schmults CD (22) Clark RA (23) Kupper TS (24) Freeman GJ (25) Mackay LK (26) Naik S (27) Newell EW (28) Elemento O (29) Suarez-Farinas M (30) Anandasabapathy N
In mice dermally infected with OVA-expressing vaccinia virus and administered OT-I cells, PD-1+ cells constituted the majority of skin OT-I Trms both during infection and after clearance. Anti-PD-1 reduced initial skin Trm formation, but did not impact later antigen recall potential, and PD-1 expression conferred a proliferative benefit in the skin, but not the LNs. DEGs from PD-1+ skin Trm were unique to this tissue site, upregulated during early Trm formation, and did not overlap with those of other T cell states. Induction of TGFβ signaling in the infection and engraftment models reversed the inhibitory effects of anti-PD-1 on skin Trm formation.
Contributed by Morgan Janes
(1) Devi KSP (2) Wang E (3) Jaiswal A (4) Konieczny P (5) Kim TG (6) Nirschl CJ (7) Verma A (8) Liu Y (9) Milczanowski J (10) Christo SN (11) Gandolfo LC (12) Haitz K (13) Vardam TD (14) Wu P (15) King SL (16) Tse SW (17) Pradhan K (18) Jiang X (19) Tian T (20) Fuhlbrigge RC (21) Schmults CD (22) Clark RA (23) Kupper TS (24) Freeman GJ (25) Mackay LK (26) Naik S (27) Newell EW (28) Elemento O (29) Suarez-Farinas M (30) Anandasabapathy N
In mice dermally infected with OVA-expressing vaccinia virus and administered OT-I cells, PD-1+ cells constituted the majority of skin OT-I Trms both during infection and after clearance. Anti-PD-1 reduced initial skin Trm formation, but did not impact later antigen recall potential, and PD-1 expression conferred a proliferative benefit in the skin, but not the LNs. DEGs from PD-1+ skin Trm were unique to this tissue site, upregulated during early Trm formation, and did not overlap with those of other T cell states. Induction of TGFβ signaling in the infection and engraftment models reversed the inhibitory effects of anti-PD-1 on skin Trm formation.
Contributed by Morgan Janes
ABSTRACT: Tissue-resident memory T (TRM) cells provide infectious, cancer and vaccine-trained immunity across barrier sites. TRM cells are implicated in autoimmunity, successful response to immune checkpoint blockade in the tumor microenvironment and toxicities that occur after immune checkpoint blockade in peripheral tissues. Here, we identified that signaling through the immune checkpoint programmed death receptor 1 (PD-1) strongly impacts the early specification of CD8+ TRM cells in the skin. PD-1 is expressed broadly across mouse and human skin TRM cells, in the absence of persistent infection, and is retained on skin TRM cells in aged mice. PD-1 supports early TRM cell colonization, skin-specific programming and silencing of other differentiation programs and promotes TGFβ responsivity and skin engraftment. Thus, PD-1 signaling mediates skin TRM cell specification during immune initiation. These findings may inform therapeutic PD-1 agonist and antagonist use to modulate successful peripheral memory.
Author Info: (1) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York,
Author Info: (1) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Immunology and Immunotherapy, Icahn School of Medicine at Mt. Sinai, New York, NY, USA. (5) Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea. (6) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (7) Institute for Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (8) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (10) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. (11) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia. Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia. (12) Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea. (13) Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA. (14) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (15) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (16) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (17) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (19) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (20) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (21) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (22) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. (23) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. (26) Department of Immunology and Immunotherapy, Icahn School of Medicine at Mt. Sinai, New York, NY, USA. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (27) Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, USA. (28) Institute for Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (29) Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Department of Dermatology, Englander Institute for Precision Medicine at Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Department of Microbiology and Immunology, Englander Institute for Precision Medicine at Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY, USA. niroananda@gmail.com.
Citation: Nat Immunol 2025 Aug 26:1339-1351 Epub07/29/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40730902
Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib
(1) Maso L (2) Rajak E (3) Hattori T (4) Hu Z (5) Koide A (6) Neel BG (7) Koide S
Demonstrating broader use of their HapImmune platform, Maso and Rajak et al. developed antibodies targeting novel “neoantigen” peptides derived from KRAS(G12C) (a cancer driver mutation) covalently bound to adagrasib (an FDA-approved KRAS inhibitor), and presented by HLA-A*03 and A*11. When incorporated into bispecific T cell engagers, these antibodies sensitized adagrasib-resistant human lung cancer cells to T cell cytotoxicity. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition that was distinct from that of sotorasib-directed HapImmune antibodies in previously published work.
Contributed by Lauren Hitchings
(1) Maso L (2) Rajak E (3) Hattori T (4) Hu Z (5) Koide A (6) Neel BG (7) Koide S
Demonstrating broader use of their HapImmune platform, Maso and Rajak et al. developed antibodies targeting novel “neoantigen” peptides derived from KRAS(G12C) (a cancer driver mutation) covalently bound to adagrasib (an FDA-approved KRAS inhibitor), and presented by HLA-A*03 and A*11. When incorporated into bispecific T cell engagers, these antibodies sensitized adagrasib-resistant human lung cancer cells to T cell cytotoxicity. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition that was distinct from that of sotorasib-directed HapImmune antibodies in previously published work.
Contributed by Lauren Hitchings
ABSTRACT: Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific antigens that are endogenously produced. HapImmuneª technology utilizes covalent inhibitors directed to an intracellular cancer driver to create cancer-specific neoantigens in the form of drug-peptide conjugates presented by class I MHC molecules. Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug-peptide/MHC complex. Thus, this technology can unite targeted and immune therapies. In the present study, we examined whether this approach could generalize to another FDA-approved KRAS(G12C) inhibitor, adagrasib, whose chemical structure and cysteine reactivity differ substantially from sotorasib. We developed antibodies selective to adagrasib-KRAS(G12C) peptides presented by HLA-A*03 and A*11 that also show cross-reactivity to other KRAS(G12C) inhibitors presented in the same manner. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition distinctly different from that of sotorasib-directed HapImmune antibodies. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development.
Author Info: (1) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Aethon Therapeutics, Long Island City, NY 11101. (2) Perlmutter Cancer Center, New York Univer
Author Info: (1) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Aethon Therapeutics, Long Island City, NY 11101. (2) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. (3) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016. (4) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. (5) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016. (6) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016. (7) Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016. Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016.
Citation: Proc Natl Acad Sci U S A 2025 Aug 5 122:e2509012122 Epub07/30/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40737322
Tumor-specific CD8 T cell characterization in HR+ breast cancer reveals an impaired antitumoral response in patients with lymph node metastasis
(1) Pinho MP (2) Antoun E (3) Sandhar B (4) Shu T (5) Gao F (6) Yang X (7) Bates A (8) Cerundolo L (9) Hamid MHBA (10) Maldonado-Perez D (11) Teague R (12) Warner E (13) Winter L (14) Alham NK (15) Verrill C (16) Lord SR (17) Rostron T (18) Clark SA (19) Waugh C (20) Sopp P (21) Conlon C (22) Fernandes RA (23) Harris AL (24) Peng Y (25) Adwani A (26) Dong T
Pinho et al. detected circulating tumor-reactive CD8+ T cell responses in the blood of patients with early-stage HR+ breast cancer by ex vivo stimulation. Circulating tumor-reactive T cells were cytotoxic, showed diverse TCR clonotypes, and some reacted to known cancer testes antigens. The presence of circulating tumor-reactive T cell responses correlated with CD8+ T cell infiltration. Patients with lymph node metastases either lacked or had a significantly lower proportions of tumor-reactive TILs. Patients with lymph node-positive HR+ breast cancer also showed lower frequencies of intratumoral neoantigen-specific CD8+ T cells in two independent scRNAseq datasets.
Contributed by Shishir Pant
(1) Pinho MP (2) Antoun E (3) Sandhar B (4) Shu T (5) Gao F (6) Yang X (7) Bates A (8) Cerundolo L (9) Hamid MHBA (10) Maldonado-Perez D (11) Teague R (12) Warner E (13) Winter L (14) Alham NK (15) Verrill C (16) Lord SR (17) Rostron T (18) Clark SA (19) Waugh C (20) Sopp P (21) Conlon C (22) Fernandes RA (23) Harris AL (24) Peng Y (25) Adwani A (26) Dong T
Pinho et al. detected circulating tumor-reactive CD8+ T cell responses in the blood of patients with early-stage HR+ breast cancer by ex vivo stimulation. Circulating tumor-reactive T cells were cytotoxic, showed diverse TCR clonotypes, and some reacted to known cancer testes antigens. The presence of circulating tumor-reactive T cell responses correlated with CD8+ T cell infiltration. Patients with lymph node metastases either lacked or had a significantly lower proportions of tumor-reactive TILs. Patients with lymph node-positive HR+ breast cancer also showed lower frequencies of intratumoral neoantigen-specific CD8+ T cells in two independent scRNAseq datasets.
Contributed by Shishir Pant
ABSTRACT: Most breast cancers express the estrogen receptor (ER), but the immune response of hormone receptor-positive (HR(+)) breast cancer remains poorly characterized. Here, dendritic cells loaded with tumor lysate are used to identify tumor-reactive CD8 T cells, which are detected in most HR(+) breast cancer patients, especially those with early-stage tumors. When present, the circulating antitumor CD8 response contains cytotoxic T cells with diverse specificity and T cell receptor (TCR) repertoire. Additionally, patients with blood cancer-specific T cells have significantly more CD8 tumor-infiltrating lymphocytes (TILs). Moreover, tumor-reactive TCR sequences are detected in the tumor, but at a significantly lower proportion in patients with lymph node involvement. Our data suggest that HR(+) breast cancer patients with lymph node metastasis lack tumor-specific CD8 T cells with capacity to infiltrate the tumor at significant levels. However, early-stage patients have a diverse antitumor CD8 response that could be harnessed to develop immunotherapeutic approaches for late-stage HR(+) patients.
Author Info: (1) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of
Author Info: (1) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (2) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (4) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (5) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (6) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (7) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (8) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. (9) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (10) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. (11) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. (12) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. (13) Department of Cellular Pathology, Oxford University NHS Foundation Trust, Oxford, UK. (14) Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK; Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. (15) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK; Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. (16) Department of Oncology, University of Oxford, Oxford, UK. (17) Sequencing Facility, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. (18) Flow Cytometry Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. (19) Flow Cytometry Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. (20) Flow Cytometry Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. (21) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (22) Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (23) Department of Oncology, University of Oxford, Oxford, UK. (24) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (25) Department of Breast Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (26) Medical Research Council Translational Immune Discovery Unit (MRC TIDU), Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. Electronic address: tao.dong@ndm.ox.ac.uk.
Citation: Cell Rep Med 2025 Jul 24 102252 Epub07/24/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40730190
Tumor-resident probiotic Clostridium butyricum improves aPD-1 efficacy in colorectal cancer models by inhibiting IL-6-mediated immunosuppression
(1) Xie M (2) Yuan K (3) Zhang Y (4) Zhang Y (5) Zhang R (6) Gao J (7) Wei W (8) Jiang L (9) Li T (10) Ding Y (11) Wang L (12) Lin Y (13) Wong CC (14) Yu J
Xie et al. found that the probiotic Clostridium butyricum was both depleted in patients with CRC and potentiated anti-PD-1 efficacy in mouse models of CRC (orthotopic MSI-H and MSS). Single-cell RNAseq showed that C. butyricum synergized with anti-PD-1 to activate cytotoxic CD8+ T cells and decrease TAM infiltration. Mechanistically, C. butyricum mediated its effect via binding of its surface protein secD to CRC-surface-expressed GRP78, resulting in downregulation of the PI3K–AKT–NF-kB pathway and reduced IL-6 secretion. Translational validation was achieved in huCD34+ humanized mice and autologous patient-derived CRC organoid–CTL cocultures.
Contributed by Katherine Turner
(1) Xie M (2) Yuan K (3) Zhang Y (4) Zhang Y (5) Zhang R (6) Gao J (7) Wei W (8) Jiang L (9) Li T (10) Ding Y (11) Wang L (12) Lin Y (13) Wong CC (14) Yu J
Xie et al. found that the probiotic Clostridium butyricum was both depleted in patients with CRC and potentiated anti-PD-1 efficacy in mouse models of CRC (orthotopic MSI-H and MSS). Single-cell RNAseq showed that C. butyricum synergized with anti-PD-1 to activate cytotoxic CD8+ T cells and decrease TAM infiltration. Mechanistically, C. butyricum mediated its effect via binding of its surface protein secD to CRC-surface-expressed GRP78, resulting in downregulation of the PI3K–AKT–NF-kB pathway and reduced IL-6 secretion. Translational validation was achieved in huCD34+ humanized mice and autologous patient-derived CRC organoid–CTL cocultures.
Contributed by Katherine Turner
ABSTRACT: Most colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy. Here, we identify Clostridium butyricum as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, C. butyricum potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that C. butyricum activates cytotoxic CD8+ T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1. Mechanistically, C. butyricum surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of C. butyricum in boosting anti-PD-1 efficacy is validated in huCD34+ humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, C. butyricum is a promising adjuvant to augment ICB therapy.
Author Info: (1) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen R
Author Info: (1) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (2) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (3) Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. (4) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (5) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (6) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (7) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (8) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (9) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (10) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (11) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (12) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (13) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. (14) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: junyu@cuhk.edu.hk.
Citation: Cancer Cell 2025 Jul 29 Epub07/29/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40780216
Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity Spotlight
(1) Ahn JJ (2) Dudics S (3) Langan DP (4) Smith JD (5) Hsu AH (6) McCright JC (7) Smith SR (8) Castleberry AL (9) George BI (10) Goitía Vázquez JA (11) Kuri PN (12) Alla SSV (13) Garcia J (14) Haider YM (15) Hamdan FW (16) Juárez JE (17) Reddy R (18) Shanmuganathan A (19) Wang Y (20) Welch A (21) Boclair D (22) Khrimian PA (23) Yaen CH (24) Mumm JB
Ahn et al. showed in vitro (using human PBMCs) and in mice that IL-10 suppressed IL-2 induction of CRS-associated cytokines by suppressing TNFα production while potentiating IL-2-mediated antitumor activities. DK210(EGFR) – a fusion protein comprising IL-2 coupled to a high-affinity IL-10 mutein targeted by an anti-EGFR scFv scaffold to tumor cells – activated CTLs and NK cells, increased perforin/granzyme B secretion, limited Treg expansion, boosted the CD8+ T cell/Treg ratio within tumors, sustained CTL functions, and enhanced efficacy in murine tumor models. In NHP, at projected therapeutic doses, DK210(EGFR) induced immune activation without inducing CRS or significant organ toxicity.
Contributed by Paula Hochman
(1) Ahn JJ (2) Dudics S (3) Langan DP (4) Smith JD (5) Hsu AH (6) McCright JC (7) Smith SR (8) Castleberry AL (9) George BI (10) Goitía Vázquez JA (11) Kuri PN (12) Alla SSV (13) Garcia J (14) Haider YM (15) Hamdan FW (16) Juárez JE (17) Reddy R (18) Shanmuganathan A (19) Wang Y (20) Welch A (21) Boclair D (22) Khrimian PA (23) Yaen CH (24) Mumm JB
Ahn et al. showed in vitro (using human PBMCs) and in mice that IL-10 suppressed IL-2 induction of CRS-associated cytokines by suppressing TNFα production while potentiating IL-2-mediated antitumor activities. DK210(EGFR) – a fusion protein comprising IL-2 coupled to a high-affinity IL-10 mutein targeted by an anti-EGFR scFv scaffold to tumor cells – activated CTLs and NK cells, increased perforin/granzyme B secretion, limited Treg expansion, boosted the CD8+ T cell/Treg ratio within tumors, sustained CTL functions, and enhanced efficacy in murine tumor models. In NHP, at projected therapeutic doses, DK210(EGFR) induced immune activation without inducing CRS or significant organ toxicity.
Contributed by Paula Hochman
ABSTRACT: Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells, mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK210 epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.
Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germa
Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germantown, MD, USA. (5) Deka Biosciences, Inc., Germantown, MD, USA. (6) Deka Biosciences, Inc., Germantown, MD, USA. (7) Deka Biosciences, Inc., Germantown, MD, USA. (8) Deka Biosciences, Inc., Germantown, MD, USA. (9) Deka Biosciences, Inc., Germantown, MD, USA. (10) Deka Biosciences, Inc., Germantown, MD, USA. (11) Deka Biosciences, Inc., Germantown, MD, USA. (12) Deka Biosciences, Inc., Germantown, MD, USA. (13) Deka Biosciences, Inc., Germantown, MD, USA. (14) Deka Biosciences, Inc., Germantown, MD, USA. (15) Deka Biosciences, Inc., Germantown, MD, USA. (16) Deka Biosciences, Inc., Germantown, MD, USA. (17) Deka Biosciences, Inc., Germantown, MD, USA. (18) Deka Biosciences, Inc., Germantown, MD, USA. (19) Deka Biosciences, Inc., Germantown, MD, USA. (20) Deka Biosciences, Inc., Germantown, MD, USA. (21) Deka Biosciences, Inc., Germantown, MD, USA. (22) Deka Biosciences, Inc., Germantown, MD, USA. (23) Deka Biosciences, Inc., Germantown, MD, USA. (24) Deka Biosciences, Inc., Germantown, MD, USA. Electronic address: mummj@dekabiosciences.com.
Citation: Cell Rep Med 2025 Jul 24 102257 Epub07/24/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40744022