Journal Articles

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

(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

(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

(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

(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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Self-adjuvanting α-helical polypeptide simultaneously delivers neoantigen mRNAs and activates dendritic cells to eradicate tumors

(1) Han J (2) Zhou J (3) Dwivedy A (4) Xue T (5) Bhatta R (6) Liu Y (7) Nguyen D (8) Bo Y (9) Wang Y (10) Wang X (11) Xu M (12) Berry M (13) Bailey K (14) Irudayaraj J (15) Liu J (16) Chen Q (17) Nie S (18) Wang X (19) Wang H

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1.

Contributed by Ute Burkhardt

(1) Han J (2) Zhou J (3) Dwivedy A (4) Xue T (5) Bhatta R (6) Liu Y (7) Nguyen D (8) Bo Y (9) Wang Y (10) Wang X (11) Xu M (12) Berry M (13) Bailey K (14) Irudayaraj J (15) Liu J (16) Chen Q (17) Nie S (18) Wang X (19) Wang H

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1.

Contributed by Ute Burkhardt

ABSTRACT: mRNA-based vaccines have demonstrated tremendous success during the era of COVID-19, but its therapeutic potential for treating cancer, especially poorly immunogenic solid tumors, remains largely underachieved. Herein, we report a class of self-adjuvanting α-helical polypeptides that can dramatically improve the antitumor efficacy of tumor neoantigen-encoding mRNAs. The α-helical polypeptides can facilitate the intracellular delivery of mRNAs into dendritic cells (DCs), simultaneously activate DCs by regulating NF-κB and IRF pathways, and improve the ability of dendritic cells to process and present mRNA-encoded neoantigens. Molecular docking and simulation results also confirm the stable complexation between mRNA and α-helical polypeptides. The conceived polyplex, upon subcutaneous administration, can migrate to the draining lymph nodes and transfect and activate DCs in the lymph nodes, resulting in superior neoantigen-specific cytotoxic T lymphocyte response in vivo. Compared to conventional lipoplexes or SM102 lipid nanoparticle-based mRNA vaccines that yield 0% tumor-free survival, the polyplex yields 83.3% and 33.3% tumor-free survival against E.G7-OVA lymphoma and 4T1 triple negative breast cancer, respectively, among the best antitumor efficacy reported to date for mRNA cancer vaccines. The polyplex also reprograms the immunosuppressive tumor microenvironment, by stimulating and enriching DCs, M1-phenotype CD86+ macrophages, and CD8+ T cells in the tumors. We also observed the upregulated expression of Programmed Death-1 (PD-1) by intratumoral CD8+ T cells and PD-L1 by 4T1 tumor cells after polyplex treatment and further demonstrated the synergistic effect between polyplex vaccine and anti-PD-1 therapy. Our polyplex system provides a facile and generalizable approach to developing robust mRNA-based cancer vaccines.

Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University o

Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (3) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (4) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (5) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (6) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (7) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (8) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (9) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (10) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (11) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (12) Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (13) Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142. (14) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL (15) Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining 314400, China. (16) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (17) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (18) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (19) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

Citation: Proc Natl Acad Sci U S A 2026 Apr 21 123:e2504976123 Epub04/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41984833

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mRNA vaccines engage unconventional pathways in CD8+ T cell priming

(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

ABSTRACT: Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8(+) T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens(1-4). However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8(+) T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8(+) T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8(+) T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8(+) T cells against antigens not encoded by the vaccine.

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis Sc

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. (3) Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (6) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (7) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (8) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (9) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (10) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (11) Innovac Therapeutics, Cambridge, MA, USA. (12) Innovac Therapeutics, Cambridge, MA, USA. (13) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. (14) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (15) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (16) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (17) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. (18) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. kmurphy@wustl.edu.

Citation: Nature 2026 Apr 15 Epub04/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41986715

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

(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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Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment Featured  

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), agonistic anti-CD40 (αCD40) reduces frequencies of intratumoral regulatory T (Treg) cells despite a lack of CD40 expression on Treg cells. Here, we leveraged spatiotemporal imaging and lineage tracing approaches to examine intratumoral Treg cell fate in a mouse model of PDAC, where immune checkpoint blockade (ICB) (αPD-1 + αCTLA-4) combined with αCD40 controls tumor growth. Intratumoral Foxp3+ Treg cell numbers collapsed upon treatment, dependent on CD40-activated dendritic cells (DCs) and induction of interleukin (IL)-12 and interferon (IFN)-γ. This reduction corresponded with cellular alterations; Treg cells acquired an "ExTreg" phenotype characterized by loss of Foxp3 expression and acquisition of T helper 1 (Th1)-like features (Tbet+IFN-γ+). αCD40 promoted a spatially reorganized tumor microenvironment (TME), with Cxcr3⁺ Treg and ExTreg cells localized to the tumor periphery with Cxcl9-expressing DCs. Through in situ analyses of T cell receptor (TCR) signaling, we found that ExTreg cells had the highest antigen-driven activation among tumor-infiltrating T cells. Reprogramming of intratumoral Treg cells into Th1-like effectors reveals plasticity and an anti-tumor capacity of these cells.

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Beth

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (2) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (4) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (5) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; Graduate Program in Biomedical Sciences, Oregon Health and Science University, Portland, OR, USA. (6) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (8) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (9) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (10) The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA. (11) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (12) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (13) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA; Center for Advanced Tissue Imaging (CAT-I), NIAID and NCI, NIH, Bethesda, MD, USA. Electronic address: rgermain@niaid.nih.gov. (14) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: byrneka@ohsu.edu.

Citation: Immunity 2026 Apr 14 59:1058-1074.e7 Epub04/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41932343

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Developing a multimodal therapy for glioblastoma using oncolytic virus delivering CD19 and EGFRvIII antigens and bi-specific CARs

Spotlight 

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

ABSTRACT: Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duar

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (3) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (4) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (5) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (6) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (7) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (8) Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (9) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (10) Cellular Immunotherapy Program Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. yshi@coh.org.

Citation: Nat Commun 2026 Apr 9 Epub04/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41957020

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PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

Spotlight 

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

ABSTRACT: While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs) with therapeutic anti-PD-1 antibodies (aPD-1), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigate ICI-bound T cells in detail using combined sequencing analysis at the single-cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we find that Tpex are enriched in proximal lymph nodes (LNs) and proliferate at a high rate after ICI treatment. Importantly, aPD-1 high-bound Tpex in LNs share T-cell receptor clonotypes with intratumoral exhausted CD8(+) T cells (Tex), suggesting their migration to tumor sites after ICI treatment. This study thus provides new insights into how ICIs enhance anti-tumor immunity by acting on Tpex in LNs, deepening our understanding of the cellular mechanisms underlying ICI therapy.

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate Sch

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (2) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Japan. (3) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. (4) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (5) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (6) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (7) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (8) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (9) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (10) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (11) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (12) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (13) Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan. (14) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (15) Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan. (16) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Department of Basic Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan. (17) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (18) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (19) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (20) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan.

Citation: Nat Commun 2026 Apr 8 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41951588

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