Journal Articles

In vivo reprogramming of cytotoxic effector CD8+ T cells via fractalkine-conjugated mRNA-LNP

Spotlight 

Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

Science immunology

Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

Contributed by Lauren Hitchings

Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

Science immunology

Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

Contributed by Lauren Hitchings

ABSTRACT: Selective in vivo reprogramming of cytotoxic effector CD8 T (Teff) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1+ Teff cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic Teff cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse Teff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood Teff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood Teff cells and detection of human CD62L+ Teff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of Teff cells.

Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania

Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 4Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 6Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Division of Animal Resources, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 9Acuitas Therapeutics, Vancouver, Canada. 10Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, USA. 11Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. 12Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Citation: Epub 2026 May 8.

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/42102231/

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    Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot Spotlight 

    (1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

    Cancer immunology research

    As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

    Contributed by Katherine Turner

    (1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

    Cancer immunology research

    As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

    Contributed by Katherine Turner

    ABSTRACT: Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, "cold" tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)-based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert "cold" tumors into inflamed "hot" lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed "hot" phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell-redirecting therapies, in challenging tumor settings.

    Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Swit

    Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Switzerland. (3) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (4) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (5) Philochem AG, Otelfingen, Switzerland. (6) Philochem AG, Otelfingen, Switzerland. (7) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (8) Philochem AG, Otelfingen, Switzerland. (9) Philochem AG, Otelfingen, Switzerland. Philogen SpA, Siena, Italy. (10) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 Philogen SpA, Siena, Italy. (11) Philochem AG, Otelfingen, Switzerland.

    Citation: Cancer Immunol Res 2026 Apr 21 OF1-OF14 Epub04/21/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42012522

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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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    IL-7/IL-15/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells enriched in long-lived T memory stem cells Spotlight 

    (1) Cole EB (2) Lamcaj S (3) Sydenstricker AV (4) Voss AG (5) Hiner CR (6) Hur HB (7) Kandpal M (8) Valderrama Pena N (9) Zheng JH (10) Xiong Y (11) Zhu Z (12) Zhang CC (13) Shrestha N (14) Dropulic B (15) Wong HC (16) Goldstein H

    Science advances | Free PMC Article

    Cole et al. used HCW9206 – a soluble tissue factor fusion protein that links IL-7, IL-15/IL-15Rα superagonist, and IL-21 – for the generation of T stem cell memory (TSCM)-enriched polyfunctional CAR T cells, without requiring anti-CD3/CD28 activation. In a humanized mouse model of HIV infection, HCW9206-stimulated duoCAR T cells (simultaneously targeting two HIV epitopes) showed superior viremia suppression compared to duoCAR TαCD3/CD28 cells. CD19 CAR THCW9206 cells exhibited increased functional persistence and elimination of an initial and subsequent rechallenge with NALM-6 leukemia cells in vivo compared to CD19 CAR TαCD3/CD28 cells.

    Contributed by Ute Burkhardt

    (1) Cole EB (2) Lamcaj S (3) Sydenstricker AV (4) Voss AG (5) Hiner CR (6) Hur HB (7) Kandpal M (8) Valderrama Pena N (9) Zheng JH (10) Xiong Y (11) Zhu Z (12) Zhang CC (13) Shrestha N (14) Dropulic B (15) Wong HC (16) Goldstein H

    Science advances | Free PMC Article

    Cole et al. used HCW9206 – a soluble tissue factor fusion protein that links IL-7, IL-15/IL-15Rα superagonist, and IL-21 – for the generation of T stem cell memory (TSCM)-enriched polyfunctional CAR T cells, without requiring anti-CD3/CD28 activation. In a humanized mouse model of HIV infection, HCW9206-stimulated duoCAR T cells (simultaneously targeting two HIV epitopes) showed superior viremia suppression compared to duoCAR TαCD3/CD28 cells. CD19 CAR THCW9206 cells exhibited increased functional persistence and elimination of an initial and subsequent rechallenge with NALM-6 leukemia cells in vivo compared to CD19 CAR TαCD3/CD28 cells.

    Contributed by Ute Burkhardt

    ABSTRACT: Functional persistence of chimeric antigen receptor T cells (CAR T cells) is limited by conventional CAR T cell manufacturing using anti-CD3/CD28 (αCD3/28) stimulation, which generates terminally differentiated and shorter-lived CAR T cells. We demonstrated that HCW9206, a unique protein scaffold linking interleukin-7 (IL-7), an IL-15/IL-15 receptor α (IL-15Rα) complex, and IL-21, generates CAR T cells without requiring αCD3/28 activation, which are highly enriched in long-lived T memory stem cells (TSCM cells) (>50%) and display potent activity across distinct disease models, HIV-1 or B cell leukemia. In a humanized mouse HIV infection model, HCW9206-generated anti-HIV duoCAR T cells suppressed viremia more effectively than αCD3/28-generated anti-HIV duoCAR T cells. In a xenograft leukemia mouse model, a recall proliferative response and complete clearance of leukemia rechallenge were displayed by HCW9206-generated but not by αCD3/28-generated anti-CD19 CAR T cells. HCW9206, a first-in-class cytokine scaffold-based platform, enables production of more potent CAR T cell-based immunotherapies by generating a CAR T cell population, which is highly functional and also markedly enriched for long-lived TSCM cells. This strategy is broadly applicable to increase persistence and functionality of CAR T cells, enhancing their efficacy for treating infectious disease and cancer.

    Author Info: (1) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (2) Department of Microbiology and Immunology, Albert Einstein College of

    Author Info: (1) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (2) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (3) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (4) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (5) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (6) RUH Bioinformatics, Center for Clinical and Translational Science, Rockefeller University Hospital, New York, NY 10065, USA. (7) RUH Bioinformatics, Center for Clinical and Translational Science, Rockefeller University Hospital, New York, NY 10065, USA. (8) HCW Biologics Inc., Miramar, FL 33025, USA. (9) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (10) Caring Cross, Gaithersburg, MD 20878, USA. (11) Caring Cross, Gaithersburg, MD 20878, USA. (12) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (13) HCW Biologics Inc., Miramar, FL 33025, USA. (14) HCW Biologics Inc., Miramar, FL 33025, USA. (15) HCW Biologics Inc., Miramar, FL 33025, USA. (16) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

    Citation: Sci Adv 2026 Mar 13 12:eaec2632 Epub03/13/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41824575

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    Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes

    Featured  

    (1) Lai J (2) Chan CW (3) Armitage JD (4) Audsley KM (5) Huang YK (6) Derrick EB (7) Carstensen LS (8) Scheffler CM (9) Jones ME (10) Sek K (11) Principe N (12) Kim JS (13) House IG (14) Chen AXY (15) Yap KM (16) Middelburg J (17) Munoz I (18) Nguyen D (19) Tong J (20) Hoang TX (21) Todd KL (22) Evrard M (23) Chee J (24) Mackay LK (25) Forrest ARR (26) Parish IA (27) Bosco A (28) Waithman J (29) Beavis PA (30) Darcy PK

    Nature immunology

    Lai, Chan, Armitage, et al. investigated whether Flt3L treatment could improve immune checkpoint blockade responses. Flt3L increased cDC1 and stem-like precursor exhausted T cells (Tpex) populations through enhanced priming in the draining lymph nodes. Combining Flt3L treatment with CTLA-4 blockade resulted in expansion of stem-like and tumor antigen-specific effector T cell populations in the tumor, resulting in improved outcomes in mouse models.

    (1) Lai J (2) Chan CW (3) Armitage JD (4) Audsley KM (5) Huang YK (6) Derrick EB (7) Carstensen LS (8) Scheffler CM (9) Jones ME (10) Sek K (11) Principe N (12) Kim JS (13) House IG (14) Chen AXY (15) Yap KM (16) Middelburg J (17) Munoz I (18) Nguyen D (19) Tong J (20) Hoang TX (21) Todd KL (22) Evrard M (23) Chee J (24) Mackay LK (25) Forrest ARR (26) Parish IA (27) Bosco A (28) Waithman J (29) Beavis PA (30) Darcy PK

    Nature immunology

    Lai, Chan, Armitage, et al. investigated whether Flt3L treatment could improve immune checkpoint blockade responses. Flt3L increased cDC1 and stem-like precursor exhausted T cells (Tpex) populations through enhanced priming in the draining lymph nodes. Combining Flt3L treatment with CTLA-4 blockade resulted in expansion of stem-like and tumor antigen-specific effector T cell populations in the tumor, resulting in improved outcomes in mouse models.

    ABSTRACT: Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.

    Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vi

    Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia. The Kids Research Institute Australia, The University of Western Australia, Perth, Western Australia, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (9) Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (11) Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (18) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (22) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. (23) Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia. (24) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. (25) Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (27) Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA. Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ, USA. (28) School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia. jason.waithman@uwa.edu.au. (29) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. paul.beavis@petermac.org. (30) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org.

    Citation: Nat Immunol 2026 Feb 10 Epub02/10/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41667622

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    Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes Spotlight 

    (1) Grassmann S (2) Santosa EK (3) Kim H (4) Johnson IB (5) Mujal AM (6) LeLuduec JB (7) Fan SX (8) Owyong M (9) Straub A (10) Deng L (11) Hsu KC (12) Busch DH (13) Lau CM (14) Sun JC

    Immunity

    Grassmann and Santosa et al. showed that temporal integration of antigen and inflammatory cytokine signals, not solely signal availability, determined lymphocyte fate. Antigen receptor engagement before IL-12 signaling initiated an adaptive NK cell response during MCMV infection, whereas IL-12 signaling without prior antigen exposure enforced terminal effector differentiation. Antigen priming led to chromatin changes that redirected STAT4 genomic binding away from ETS/RUNX motifs and toward AP-1 binding sites. In CD8+ T cells, AP-1/STAT4 cooperation depended on TCR avidity and signal strength, and determined effector versus memory differentiation.

    Contributed by Shishir Pant

    (1) Grassmann S (2) Santosa EK (3) Kim H (4) Johnson IB (5) Mujal AM (6) LeLuduec JB (7) Fan SX (8) Owyong M (9) Straub A (10) Deng L (11) Hsu KC (12) Busch DH (13) Lau CM (14) Sun JC

    Immunity

    Grassmann and Santosa et al. showed that temporal integration of antigen and inflammatory cytokine signals, not solely signal availability, determined lymphocyte fate. Antigen receptor engagement before IL-12 signaling initiated an adaptive NK cell response during MCMV infection, whereas IL-12 signaling without prior antigen exposure enforced terminal effector differentiation. Antigen priming led to chromatin changes that redirected STAT4 genomic binding away from ETS/RUNX motifs and toward AP-1 binding sites. In CD8+ T cells, AP-1/STAT4 cooperation depended on TCR avidity and signal strength, and determined effector versus memory differentiation.

    Contributed by Shishir Pant

    ABSTRACT: Lymphocyte differentiation during infection depends on the integration of antigen and cytokine signals, yet how the timing and sequence of these cues program cell fate remains unclear. We found that interleukin-12 (IL-12) plays a context-dependent role in immune memory formation. Without prior antigen-receptor signaling, IL-12 drove cytotoxic lymphocytes toward terminal effector differentiation. In contrast, antigen signaling redirected IL-12-STAT4 activity through cooperation with AP-1 transcription factors to promote memory formation. This stepwise signal integration enabled lymphocytes to acquire memory rather than effector fates. Whereas CD8(+) T cells were protected from premature IL-12 signaling by delayed receptor expression, natural killer (NK) cells, which constitutively express the IL-12 receptor, must engage their antigen receptor before cytokine signaling for efficient adaptive programming. Together, these findings define a framework in which sequential antigen and cytokine signaling coordinates effector versus memory differentiation, ensuring both robust primary responses and selective enrichment of high-avidity memory clones.

    Author Info: (1) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: grassmas@mskcc.org. (2) Immunology Program, Memorial Sloan Kettering Ca

    Author Info: (1) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: grassmas@mskcc.org. (2) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (3) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (5) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (8) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (9) Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany. (10) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. (11) Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. (12) Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany; German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany. (13) Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. (14) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.

    Citation: Immunity 2026 Jan 30 Epub01/30/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41619729

    Tags:

    Type I interferon restricts mRNA vaccine efficacy through suppression of antigen uptake in cDCs Spotlight 

    (1) Lobb TA (2) Dickson A (3) Guo W (4) Beeram S (5) Carrero JA (6) Dalben Y (7) DiPaolo RJ (8) Alspach E (9) Tse LV (10) Ferris ST

    NPJ vaccines

    Lobb et al. showed that IFN-I pretreatment of DCs in vitro abrogated DC uptake/expression of mRNA-LNPs, and that mRNA-LNP vaccination of mice induced IFN-I transiently. Prior disruption of IFN-I signaling enhanced splenic DC uptake/expression of vaccine, and CD8⁺ T cell priming. IFN-I signaling induced by GFP (mock) vaccination 24 hr prior to vaccination with antigen reduced DC uptake of mRNA-LNPs, and cDC1-dependent CD8⁺ T cell responses. Inhibition of IFNAR signaling alone enhanced effector function and tumor control by vaccine-induced CD8+ T cells, and restored antiviral responses in models not impacted by other virus-induced cytokines.

    Contributed by Paula Hochman

    (1) Lobb TA (2) Dickson A (3) Guo W (4) Beeram S (5) Carrero JA (6) Dalben Y (7) DiPaolo RJ (8) Alspach E (9) Tse LV (10) Ferris ST

    NPJ vaccines

    Lobb et al. showed that IFN-I pretreatment of DCs in vitro abrogated DC uptake/expression of mRNA-LNPs, and that mRNA-LNP vaccination of mice induced IFN-I transiently. Prior disruption of IFN-I signaling enhanced splenic DC uptake/expression of vaccine, and CD8⁺ T cell priming. IFN-I signaling induced by GFP (mock) vaccination 24 hr prior to vaccination with antigen reduced DC uptake of mRNA-LNPs, and cDC1-dependent CD8⁺ T cell responses. Inhibition of IFNAR signaling alone enhanced effector function and tumor control by vaccine-induced CD8+ T cells, and restored antiviral responses in models not impacted by other virus-induced cytokines.

    Contributed by Paula Hochman

    ABSTRACT: Type I interferons (IFN) are key mediators of innate immune activation, promoting upregulation of costimulatory molecules and Major Histocompatibility Complex (MHC) I/II on antigen-presenting cells (APCs). However, IFN also suppress endogenous translation to restrict viral replication. Critically, IFN-stimulated APCs lose the capacity to acquire new antigens, making the timing of IFN signaling a crucial determinant of vaccine efficacy. Here, we show that both DC-specific loss of IFNα/β receptor (IFNαR) and transient blockade of IFNαR before vaccination enhances vaccine uptake and expression within DCs, improves CD8⁺ T cell priming, and leads to superior tumor control. We also demonstrate that IFN signaling before vaccination, triggered by prior infection or administration of a different vaccine, impairs dendritic cell uptake of mRNA-LNP vaccines and reduces the magnitude of vaccine-specific CD8⁺ T cell responses. These findings highlight the dual-edged nature of IFN signaling and offer a potential strategy for enhancing vaccine-induced immunity.

    Author Info: (1) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (2) Department of Immunology and Microbiology, University of

    Author Info: (1) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (2) Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (4) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (5) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (6) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (7) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (8) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (9) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (10) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. stephen.ferris@health.slu.edu.

    Citation: NPJ Vaccines 2026 Jan 5 Epub01/05/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41486285

    Tags:

    DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity

    Spotlight 

    (1) Stockmann AP (2) Vincent S (3) Herschelman L (4) Huang CS (5) Ma J (6) Fallon D (7) Kirby P (8) Gutierrez E (9) Talbot D (10) Hicks SW (11) Wagtmann N (12) Cheung AF

    Cell reports. Medicine

    Stockmann et al. engineered DF6215, comprised of two truncated IgG1 Fc chains (which bind FcRn, but not FcγR) fused at one Fc C terminus to an IL-2 mutein with reduced IL-2Rα (modest) and IL-2Rαβγ (23-fold) binding, increased IL-2Rβ binding (3.5-fold), and enhanced IL-2Rβγ signaling compared to WT IL-2. DF6215 preferentially expanded murine tumor-infiltrating CD8+ T and NK cells over Tregs, induced robust dose-dependent regression of solid tumors as monotherapy, and synergized with anti-PD-1. In NHPs, DF6215 showed an extended serum half-life and favorable safety and pharmacodynamics relative to aldesleukin. DF6215 is now in Phase 1/2 testing.

    Contributed by Paula Hochman

    (1) Stockmann AP (2) Vincent S (3) Herschelman L (4) Huang CS (5) Ma J (6) Fallon D (7) Kirby P (8) Gutierrez E (9) Talbot D (10) Hicks SW (11) Wagtmann N (12) Cheung AF

    Cell reports. Medicine

    Stockmann et al. engineered DF6215, comprised of two truncated IgG1 Fc chains (which bind FcRn, but not FcγR) fused at one Fc C terminus to an IL-2 mutein with reduced IL-2Rα (modest) and IL-2Rαβγ (23-fold) binding, increased IL-2Rβ binding (3.5-fold), and enhanced IL-2Rβγ signaling compared to WT IL-2. DF6215 preferentially expanded murine tumor-infiltrating CD8+ T and NK cells over Tregs, induced robust dose-dependent regression of solid tumors as monotherapy, and synergized with anti-PD-1. In NHPs, DF6215 showed an extended serum half-life and favorable safety and pharmacodynamics relative to aldesleukin. DF6215 is now in Phase 1/2 testing.

    Contributed by Paula Hochman

    ABSTRACT: DF6215 is a rationally engineered interleukin-2 (IL-2) Fc-fusion protein developed to overcome efficacy and safety limitations of traditional IL-2 cancer immunotherapy. Unlike non-alpha (non-α) IL-2 variants that eliminate CD25 binding and underperform clinically, DF6215 retains moderate IL-2 receptor α (IL-2Rα) affinity while enhancing IL-2Rβγ signaling and extending the half-life via an engineered immunoglobulin (Ig)G1 Fc domain. This design preferentially expands cytotoxic CD8+ T cells and natural killer cells over regulatory T cells, resulting in favorable effector-to-regulatory cell ratios, enhanced immune activation, and robust tumor regression in mouse models. In poorly immunogenic tumors, DF6215 synergized with PD-1 blockade to achieve durable responses without added toxicity. Cynomolgus monkey studies confirm DF6215's pharmacodynamics and favorable safety profile, with no signs of vascular leak syndrome or cytokine release syndrome. These findings position DF6215 as a differentiated IL-2 capable of modulating the tumor microenvironment and achieving potent anti-tumor immunity with improved tolerability, supporting its advancement into clinical trials for solid tumors.

    Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dr

    Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (5) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (6) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (7) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (8) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (9) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (10) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (11) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (12) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. Electronic address: ann.cheung@dragonflytx.com.

    Citation: Cell Rep Med 2025 Dec 29 102518 Epub12/29/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41468896

    Tags:

    Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity

    Spotlight 

    (1) Gorline L (2) do Carmo FLR (3) Bourdely P (4) Bornres J (5) Vaudiau N (6) Semervil A (7) Vetillard M (8) Coulibaly ASK (9) Jugniot N (10) Ok A (11) Bausart M (12) Fiquet O (13) Andrade M (14) Fardol D (15) Haddar I (16) Abou Nader Z (17) Weber J (18) Theobald H (19) Collin M (20) Calmette J (21) Anselmi G (22) Fico F (23) Ginhoux F (24) Majlessi L (25) Gautier EL (26) Saveanu L (27) Helft J (28) Dalod M (29) Dusseaux M (30) Di Santo JP (31) Hugues S (32) Guermonprez P

    Nature communications

    To overcome active inhibition of cDC1 recruitment to tumors, Gorline and Rosa do Carmo et al. showed that mesenchymal stromal cells (MSC), engineered to express the membrane-bound form of FLT3L and delivered intratumorally, required pIC activation of CCL5 and CXCL9 to enhance the migration of DCs into tumors and to draining lymph nodes. Antigen cross-presentation, infiltration of T and NK cells, T cell activation, and synergy with ICB were all increased. Expression of the chemokines in the FLT3L-engineered MSC replaced the need for pIC, replicating the benefit. Engineered MSCs expressing the human factors enhanced DC engraftment in a humanized mouse model.

    Contributed by Ed Fritsch

    (1) Gorline L (2) do Carmo FLR (3) Bourdely P (4) Bornres J (5) Vaudiau N (6) Semervil A (7) Vetillard M (8) Coulibaly ASK (9) Jugniot N (10) Ok A (11) Bausart M (12) Fiquet O (13) Andrade M (14) Fardol D (15) Haddar I (16) Abou Nader Z (17) Weber J (18) Theobald H (19) Collin M (20) Calmette J (21) Anselmi G (22) Fico F (23) Ginhoux F (24) Majlessi L (25) Gautier EL (26) Saveanu L (27) Helft J (28) Dalod M (29) Dusseaux M (30) Di Santo JP (31) Hugues S (32) Guermonprez P

    Nature communications

    To overcome active inhibition of cDC1 recruitment to tumors, Gorline and Rosa do Carmo et al. showed that mesenchymal stromal cells (MSC), engineered to express the membrane-bound form of FLT3L and delivered intratumorally, required pIC activation of CCL5 and CXCL9 to enhance the migration of DCs into tumors and to draining lymph nodes. Antigen cross-presentation, infiltration of T and NK cells, T cell activation, and synergy with ICB were all increased. Expression of the chemokines in the FLT3L-engineered MSC replaced the need for pIC, replicating the benefit. Engineered MSCs expressing the human factors enhanced DC engraftment in a humanized mouse model.

    Contributed by Ed Fritsch

    ABSTRACT: Tumor infiltration by XCR1⁺ conventional dendritic cells (cDC1) correlates strongly with favorable prognosis and improved responses to immunotherapy. Yet, tumor-driven immunosuppressive programs restrict efficient cDC1 recruitment, highlighting the need for strategies to increase cDC1 access to the tumor microenvironment. Here, we establish a proof-of-concept cell-based immunotherapy that enhances the infiltration of circulating cDC1 progenitors and supports their local expansion. Intratumoral engraftment of autologous mesenchymal stromal cells engineered to express membrane bound FLT3L promotes cDC1 recruitment when combined with poly(I:C). We identify poly(I:C)-induced CXCL9 and CCL5 as essential chemokines controlling intratumoral cDC1 infiltration. Stromal cell-mediated local delivery of FLT3L together with CXCL9 and CCL5 is sufficient to enhance cDC1 infiltration in mice or humanized mice settings. Finally, this approach activates antitumor immunity and partially overcomes resistance to immune checkpoint blockade. Collectively, our data support the therapeutic potential of expanding intratumoral cDC1s through local and sustained delivery of FLT3L, CXCL9, and CCL5.

    Author Info: (1) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells

    Author Info: (1) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (2) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (3) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, UniversitŽ Paris CitŽ, Paris, France. (4) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (5) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (6) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, UniversitŽ Paris CitŽ, Paris, France. (7) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, UniversitŽ Paris CitŽ, Paris, France. (8) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (9) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (10) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, UniversitŽ Paris CitŽ, Paris, France. (11) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (12) Human Disease Models Core Facility, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (13) Human Disease Models Core Facility, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (14) Nutrition and Obesity: Systemic Approaches, Inserm, Sorbonne University, Paris, France. (15) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (16) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, UniversitŽ Paris CitŽ, Paris, France. (17) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, UniversitŽ Paris CitŽ, Paris, France. (18) Inserm U1015, Institut Gustave Roussy, UniversitŽ Paris-Saclay, Villejuif, France. (19) Inserm Transfert, Paris, France. (20) Inserm Transfert, Paris, France. (21) Deparment of Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. (22) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (23) Inserm U1015, Institut Gustave Roussy, UniversitŽ Paris-Saclay, Villejuif, France. (24) Virology Department, Pasteur-TheraVectys Joint Laboratory, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (25) Nutrition and Obesity: Systemic Approaches, Inserm, Sorbonne University, Paris, France. (26) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, UniversitŽ Paris CitŽ, Paris, France. (27) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, UniversitŽ Paris CitŽ, Paris, France. (28) Centre d'Immunologie de Marseille-Luminy, CIML, CNRS, INSERM, Aix Marseille UniversitŽ, Marseille, France. (29) Human Disease Models Core Facility, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (30) Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. Immunology Department, ImmunitŽ InnŽe, Institut Pasteur, Paris, France. (31) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (32) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. pierre.guermonprez@pasteur.fr. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, UniversitŽ de Paris CitŽ, Paris, France. pierre.guermonprez@pasteur.fr. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. pierre.guermonprez@pasteur.fr.

    Citation: Nat Commun 2025 Dec 30 Epub12/30/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41469380

    Tags:

    IL-12 and GM-CSF engineered dendritic cells enhance the enrichment and selection of tumor-reactive T cells for cancer immunotherapy

    (1) Liu Z (2) Li H (3) Gao Z (4) Cheng R (5) Lu J (6) Che X (7) Dong J (8) Wang Z (9) Cui Z (10) Gu J (11) Bai Y (12) Li C (13) Liu Y (14) Wang C (15) Deng H

    Frontiers in immunology | Free PMC Article

    (1) Liu Z (2) Li H (3) Gao Z (4) Cheng R (5) Lu J (6) Che X (7) Dong J (8) Wang Z (9) Cui Z (10) Gu J (11) Bai Y (12) Li C (13) Liu Y (14) Wang C (15) Deng H

    Frontiers in immunology | Free PMC Article

    The use of tumor-reactive T cells in targeted tumor elimination holds significant potential for cancer immunotherapy, such as Tumor-Infiltrating Lymphocyte (TIL) therapy and TCR-T adoptive immunotherapy. Critical aspects of the effective clinical application of these immunotherapies include the enrichment and selection of tumor antigens and their corresponding reactive T cells. However, current in vitro methods for expanding and screening tumor antigen-reactive T cells remain inefficient. One reason for this inefficiency is the dysfunctional state of tumor-reactive T cells, which limits their expansion and activation. To address this challenge, we developed an optimized dendritic cell-based culture system, in which dendritic cells simultaneously express interleukin-12 and granulocyte-macrophage colony-stimulating factor (12GM-DCs), to enhance the expansion of tumor-reactive T cells. We found that 12GM-DCs can enrich reactive T cells targeting various tumor antigens, including virus-associated tumor antigens, tumor-associated antigens, mutant tumor neoantigens, and patient-specific tumor neoantigens. Moreover, 12GM-DCs increased the proportion of antigen-specific T cells, enhanced the activation of those T cells, and promoted the maintenance of a memory phenotype. The cytotoxicity of these antigen-reactive T cells was increased after co-culture with 12GM-DCs, likely due to the increased secretion of interferon-_ and granzyme B. Importantly, these functions and phenotypic advantages of tumor antigen-reactive T cells derived from the 12GM-DC culture system could be effectively maintained and the antitumor activity was also enhanced in tumor-burden mice. Our 12GM-DC coculture system effectively enriches antigen-specific T cells and has the potential to advance the clinical application of cancer immunotherapy by targeting tumor antigens and their reactive T cells.

    Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (2) Depa

    Author Info: (1) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (2) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. (3) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (4) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (5) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (6) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (7) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (8) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (9) School of Life Sciences, Peking University, Beijing, China. (10) Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China. (11) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (12) School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. (13) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. (14) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. School of Life Sciences, Peking University, Beijing, China. (15) Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China. Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing, China. Changping Laboratory, MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

    Citation: Front Immunol 2025 16:1684842 Epub11/17/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41333469

    Tags:
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