Journal Articles

Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1

(1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

Nature

Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

(1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

Nature

Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

ABSTRACT: Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer(1). Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1_mg_kg(-1)) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3_mg_kg(-1)) or intravenous ipilimumab (3_mg_kg(-1)). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (T(reg)) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural T(reg) cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fc_ receptor (Fc_R) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated T(reg) cell and Fc_R(+) M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie I

Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (2) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (3) Gustave Roussy, Service de Biostatistiques et d'EpidŽmiologie (SBE), UniversitŽ Paris Saclay, Villejuif, France. INSERM U1018, ONCOSTAT, Equipe LabellisŽe Ligue contre le Cancer, Villejuif, France. (4) INSERM U981, Gustave Roussy, Villejuif, France. (5) Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (6) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. (7) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (8) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (9) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (10) Gustave Roussy, DŽpartement d'Imagerie MŽdicale, Villejuif, France. (11) Gustave Roussy, Service de Promotion d'Etudes Cliniques, DRC, Villejuif, France. (12) INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (13) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (14) INSERM CIC 1428, BIOTHERIS, Villejuif, France. (15) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (16) Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (17) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (18) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (19) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U1015, Immunologie des tumeurs et immunothŽrapie contre le cancer, Villejuif, France. (20) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (21) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, Service de Pharmacologie, DŽpartement de Biologie et Pathologie mŽdicales, Villejuif, France. (22) INSERM CIC 1428, BIOTHERIS, Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (23) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (24) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (25) INSERM U981, Gustave Roussy, Villejuif, France. (26) CHU de Toulouse, Service d'Oncodermatologie, IUCT-O, Toulouse, France. INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France. UniversitŽ Toulouse III - Paul Sabatier, DŽpartement de Dermatologie, Toulouse, France. (27) UniversitŽ Paris CitŽ, AP-HP Dermato-oncologie et CIC, Institut du Cancer APHP nord, Paris, France. INSERM U1342-Equipe 1-CNRS EMR8000, H™pital Saint Louis, Paris, France. (28) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. INSERM U1052-CNRS UMR5286, PlasticitŽ Tumorale dans le MŽlanome, Centre de Recherche en CancŽrologie de Lyon, Centre LŽon BŽrard, Lyon, France. UniversitŽ Claude Bernard Lyon 1, Lyon, France. (29) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (30) INSERM CIC 1428, BIOTHERIS, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. aurelien.marabelle@gustaveroussy.fr. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. aurelien.marabelle@gustaveroussy.fr.

Citation: Nature 2026 Apr 29 Epub04/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056527

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The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion Spotlight 

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

ABSTRACT: The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical O

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (3) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (5) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (6) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (7) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (8) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (9) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (11) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (12) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (13) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (14) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. (15) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (16) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (17) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (18) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (19) Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, USA. (20) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (21) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (22) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (23) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (24) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (25) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (26) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (27) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (28) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (29) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.

Citation: Dev Cell 2026 Apr 28 Epub04/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42055006

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Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma Spotlight 

(1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

Journal for immunotherapy of cancer | Free PMC Article

Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

Contributed by Alex Najibi

(1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

Journal for immunotherapy of cancer | Free PMC Article

Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

Contributed by Alex Najibi

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown. METHODS: We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay. RESULTS: Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T_cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T_cells (p=0.06). CONCLUSIONS: Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (3) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (4) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (5) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (6) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (7) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (8) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (9) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (10) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (11) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (12) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (13) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (14) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (15) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (16) F Hoffmann-La Roche Ltd, Basel, Switzerland. (17) F Hoffmann-La Roche Ltd, Basel, Switzerland. Genentech Inc, South San Francisco, California, USA. (18) Genentech Inc, South San Francisco, California, USA. (19) Genentech Inc, South San Francisco, California, USA. (20) Genentech Inc, South San Francisco, California, USA. (21) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Ludwig Institute for Cancer Research, Baltimore, Maryland, USA. (22) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (23) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (24) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (25) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (26) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (27) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (28) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu. (29) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu.

Citation: J Immunother Cancer 2026 Apr 21 14: Epub04/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42014205

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Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity Spotlight 

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

ABSTRACT: Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (AT(EVs)) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. AT(EV)-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EV(DNA)), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by AT(EVs) disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EV(DNA) encoding APP genes. DNase treatment removes most AT-EV(DNA), abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, AT(EVs) hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by AT(EVs) that boosts APP and anti-tumor immunity while limiting autoimmunity.

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. (2) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (5) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Systems Biology, Columbia University, New York, NY, USA. (8) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. (10) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linkšping University, Linkšping, Sweden. (11) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (12) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (13) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (14) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (15) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (16) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (17) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (19) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (20) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (21) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (23) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (24) Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA. (25) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (27) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Pathology, University of California, San Diego, La Jolla, CA, USA. (29) Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium. (30) Laboratory of Biology of Tumor and Development, UniversitŽ de Lige, Lige, Belgium. (31) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (32) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (33) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA. (34) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (35) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (37) Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (38) Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA. (39) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (40) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (41) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. (42) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (43) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: haz2005@med.cornell.edu. (44) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: irm2224@med.cornell.edu. (45) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

Citation: Cancer Cell 2026 Apr 30 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066762

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Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors

Featured  

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

ABSTRACT: Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (T(reg) cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I(+) cancers that expressed NKG2D ligands. T(reg) cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-T(reg) cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-T(reg) cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of T(reg) cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of T(reg) cells in tumors can control CD8 T cell-resistant cancers.

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electric

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (7) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (8) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (9) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (10) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (11) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (12) Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94305, USA. (13) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (14) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (15) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Citation: Sci Immunol 2026 Apr 10 11:eadx4411 Epub04/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41961946

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Debio 1562M CD37-targeting ADC is highly active and well tolerated in preclinical models of AML and MDS Spotlight 

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

ABSTRACT: The leukocyte antigen CD37 is broadly expressed on acute myeloid leukemia (AML) blasts and associated with poor prognosis. We demonstrate that myelodysplastic syndrome (MDS) cells also express CD37, and both AML and MDS cells have favorable internalization properties of this receptor. Debio 1562M is a next-generation antibody-drug conjugate (ADC) that targets CD37 and is optimized to deliver more toxins to tumor cells than the first-generation ADC Debio 1562, while maintaining a good safety profile. Preclinically, Debio 1562M showed robust anti-leukemic activity in AML and MDS primary samples and in AML xenograft models, irrespective of disease stage or genotype. Debio 1562M was able to target leukemic stem cells in vitro and significantly decrease tumor burden in blood and bone marrow, resulting in survival prolongation compared with standard-of-care treatments. These data demonstrate that CD37 is a relevant target for both indications and that Debio 1562M is a promising therapeutic candidate.

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausann

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausanne, Switzerland. (4) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (5) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (6) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (7) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (8) Debiopharm International SA, 1006 Lausanne, Switzerland. (9) Debiopharm International SA, 1006 Lausanne, Switzerland. (10) Debiopharm International SA, 1006 Lausanne, Switzerland. (11) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (12) Debiopharm International SA, 1006 Lausanne, Switzerland. Electronic address: lisa.ivanschitz@debiopharm.com.

Citation: Cell Rep Med 2026 Apr 20 102749 Epub04/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42013843

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Spleen-targeted neoantigen mRNA vaccine induces ISG15+ CD8+ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma

Spotlight 

(1) Lin X (2) Chen G (3) Tang R (4) Wu M (5) Zhang D (6) Lin F (7) Guan J (8) Yang J (9) Dong X (10) Zheng X (11) Qiu L (12) Yu H (13) Cai Z (14) Liu X

Cell reports. Medicine

Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens.

Contributed by Shishir Pant

(1) Lin X (2) Chen G (3) Tang R (4) Wu M (5) Zhang D (6) Lin F (7) Guan J (8) Yang J (9) Dong X (10) Zheng X (11) Qiu L (12) Yu H (13) Cai Z (14) Liu X

Cell reports. Medicine

Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens.

Contributed by Shishir Pant

ABSTRACT: The efficacy of neoantigen vaccine for advanced hepatocellular carcinoma (HCC) is limited largely due to insufficient T cell mobilization and activation. Herein, we develop a spleen-targeted neoantigen mRNA vaccine (STNvac) with highly efficient spleen-selective mRNA transfection. Using a three-dose vaccination regimen, STNvac demonstrates remarkable therapeutic efficacy in orthotopic HCC model with a high likelihood of complete tumor regression and significantly improved survival rates (p < 0.0001). Notably, we identify a distinct ISG15(+) CD8(+) T cell population as crucial mediators of STNvac-induced immunity with potent antigen-processing and cytotoxic capacities. Intriguingly, STNvac promotes the formation of tertiary lymphoid structures (TLSs) through GZMA-F2R-mediated interactions between ISG15(+) CD8(+) T cells and antigen-presenting cells (APCs), which is also confirmed in HCC patients. Taken together, our findings demonstrate the potent antitumor efficacy of spleen-targeted mRNA vaccine and reveal its underlying immune cell interactive mechanisms, presenting high potential for clinical translation.

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 35000

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (2) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (5) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (6) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (12) State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. (13) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: caizhixiong1985@163.com. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: xiaoloong.liu@gmail.com.

Citation: Cell Rep Med 2026 Apr 20 102754 Epub04/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42013842

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Allogeneic CD19 CAR T cells armed with an anti-rejection CD70 CAR overcome antigen escape and evade alloimmune responses Spotlight 

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells eliminated B cells and CD70(+) T cells derived from patients with systemic lupus erythematosus in humanized mouse models, resulting in reduced immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore broaden clinical applicability while enabling the use of less intensive lymphodepleting conditioning regimens prior to CAR T cell infusion.

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA,

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA, USA. (4) Allogene Therapeutics Inc., South San Francisco, CA, USA. (5) Allogene Therapeutics Inc., South San Francisco, CA, USA. (6) Allogene Therapeutics Inc., South San Francisco, CA, USA. (7) Allogene Therapeutics Inc., South San Francisco, CA, USA. (8) Allogene Therapeutics Inc., South San Francisco, CA, USA. (9) Allogene Therapeutics Inc., South San Francisco, CA, USA. (10) Allogene Therapeutics Inc., South San Francisco, CA, USA. (11) Allogene Therapeutics Inc., South San Francisco, CA, USA. cesar.sommer@allogene.com. (12) Allogene Therapeutics Inc., South San Francisco, CA, USA. elvin.lauron@allogene.com.

Citation: Nat Commun 2026 Apr 12 Epub04/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41965340

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Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression Spotlight 

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

ABSTRACT: Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8(+), TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to OX40 and PD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8(+) effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (13) Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27705, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. (17) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (18) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (19) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (20) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (21) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (22) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. (23) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (24) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (25) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63108, USA. (26) Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea. (27) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (28) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (29) UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (30) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (31) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (33) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (34) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Citation: Cancer Cell 2026 Apr 16 Epub04/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41997138

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Immune-induced TCR-like antibodies regulate specific T cell response in mice Spotlight 

(1) Kishida K (2) Kawakami K (3) Tanabe H (4) Nakai W (5) Yonekura K (6) Yokoyama S (7) Arase H

Nature communications | Free PMC Article

Kishida et al. showed that immune-induced TCR-like antibodies (iTabs) – antibodies that are specific to an antigen peptide–MHC-II complex – were produced during helper T cell responses to immunization with various antigens. These iTabs induced antigen-dependent depletion of target cells, blocked TCR recognition of specific peptide–MHC-II complexes, and prevented activation of antigen-specific T cells, but only when the presented peptides contained specific flanking residues. In a mouse model, treatment with iTabs or immunization with a peptide that induced iTabs effectively limited the development of autoimmune encephalomyelitis.

Contributed by Lauren Hitchings

(1) Kishida K (2) Kawakami K (3) Tanabe H (4) Nakai W (5) Yonekura K (6) Yokoyama S (7) Arase H

Nature communications | Free PMC Article

Kishida et al. showed that immune-induced TCR-like antibodies (iTabs) – antibodies that are specific to an antigen peptide–MHC-II complex – were produced during helper T cell responses to immunization with various antigens. These iTabs induced antigen-dependent depletion of target cells, blocked TCR recognition of specific peptide–MHC-II complexes, and prevented activation of antigen-specific T cells, but only when the presented peptides contained specific flanking residues. In a mouse model, treatment with iTabs or immunization with a peptide that induced iTabs effectively limited the development of autoimmune encephalomyelitis.

Contributed by Lauren Hitchings

ABSTRACT: Antigen-specific regulation of T cell response is crucial for limiting hyperimmune response. However, the molecular mechanisms governing specific immune regulation remain unclear. In this study, we discover that antibodies specific to the antigen peptide-MHC class II complex are produced during helper T cell responses to various antigens, including hen egg lysozyme and proteolipid protein peptide. These antibodies specifically inhibit T cell receptor (TCR) recognition of MHC class II molecules presenting specific antigen peptide. We term these antibodies 'immune-induced TCR-like antibodies' or iTabs. Immunization with peptides containing flanking residues induces iTabs whereas immunization with peptides lacking flanking residues does not. Furthermore, we show that immunization with iTab-inducible peptide or iTab treatment suppress autoimmune disease development in a mouse model of experimental autoimmune encephalomyelitis. Thus, our findings provide a strategy for suppressing antigen-specific helper T cell responses using specific peptides, potentially controlling autoimmune diseases.

Author Info: (1) Department of Immunochemistry, Research Institute for Microbial Diseases, The University of Osaka, Suita, Osaka, Japan. (2) Biostructural Mechanism Group, RIKEN SPring-8 Center

Author Info: (1) Department of Immunochemistry, Research Institute for Microbial Diseases, The University of Osaka, Suita, Osaka, Japan. (2) Biostructural Mechanism Group, RIKEN SPring-8 Center, Hyogo, Japan. (3) Department of Drug Target Protein Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan. Department of Structural Biology and Biochemistry, Institute of New Industry Incubation, Institute of Science Tokyo, Tokyo, Japan. (4) Department of Immunochemistry, Research Institute for Microbial Diseases, The University of Osaka, Suita, Osaka, Japan. Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan. (5) Biostructural Mechanism Group, RIKEN SPring-8 Center, Hyogo, Japan. Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi, Japan. (6) Department of Drug Target Protein Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan. Department of Structural Biology and Biochemistry, Institute of New Industry Incubation, Institute of Science Tokyo, Tokyo, Japan. (7) Department of Immunochemistry, Research Institute for Microbial Diseases, The University of Osaka, Suita, Osaka, Japan. arase@biken.osaka-u.ac.jp. Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Osaka, Japan. arase@biken.osaka-u.ac.jp. Center for Advanced Modalities and DDS, The University of Osaka, Suita, Osaka, Japan. arase@biken.osaka-u.ac.jp. Center for Infectious Disease Education and Research, The University of Osaka, Suita, Osaka, Japan. arase@biken.osaka-u.ac.jp.

Citation: Nat Commun 2026 Apr 16 17: Epub04/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41991935

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