Journal Articles

FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight 

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC. METHODS: Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing. RESULTS: Combination therapy induced dense intratumoral clusters of CD4(+) and CD8(+) T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4(+) and CD8(+) T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4(+) T cells toward a T helper cell 1 phenotype in combination-treated tumors. CONCLUSION: The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Ba

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (5) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (6) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Institute of Experimental Immunology, UniversitŠt ZŸrich, ZŸrich, Switzerland. Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany. (12) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (13) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland leo.kunz@roche.com.

Citation: J Immunother Cancer 2026 May 28 14: Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42208978

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Targeting CCR1 remodels the tumor microenvironment and relieves immune suppression in pancreatic cancer Featured  

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8+ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

(1) Zhang Y (2) Kadiyala P (3) Yan W (4) Brown K (5) Avritt FR (6) Donahue KL (7) Procario MC (8) Okoye JO (9) Giridharan T (10) Elhossiny AM (11) Espinoza CE (12) Awad D (13) Lasse Opsahl EL (14) Medina-Cabrera PI (15) Velez-Delgado A (16) Menjivar RE (17) Yang OA (18) Yang S (19) He X (20) Gupta S (21) Tariq R (22) Brandt AR (23) Wang X (24) denDekker A (25) Nwosu ZC (26) Carpenter ES (27) Courtney AH (28) Bednar F (29) Frankel TL (30) Lyssiotis CA (31) Zheng B (32) Kryczek I (33) Pasca di Magliano M

Cancer immunology research

Evaluating the role of CCR1 in pancreatic cancer, Zhang et al. used KC and KPC mouse tumor models, and found while elimination of CCR1 did not limit tumor formation, it delayed progression of active disease, resulting in prolonged survival. CCR1 was mainly expressed by macrophages and granulocytes, but its deletion induced TIME remodeling that affected fibroblasts and increased CD8+ T cell accumulation, but not activation. CCR1 inhibition showed synergy in combination with targeting of other immunosuppressive mechanisms, though there was still room to improve antitumor efficacy in this highly resistant tumor setting.

ABSTRACT: A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid-cell driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the functional role of CCR1, we generated oncogenic KRAS based genetically engineered mouse models of pancreatic cancer, with or without addition of a mutant form of the tumor suppressor Trp53 (KC and KPC, respectively), lacking CCR1 expression. CCR1 inactivation did not affect formation of early lesions, but delayed progression to cancer and resulted in prolonged survival. In these mice, macrophages lacking CCR1 had reduced expression of the immunosuppressive marker Arginase 1. Loss of CCR1 also profoundly shifted the prevalent fibroblast population, inducing a pancreatic stellate cell-like phenotype. In two independent syngeneic orthotopic models, ablation or pharmacologic inhibition of CCR1 reduced tumor growth and increased CD8+ T cell cytotoxic activity, sensitizing tumors to immunotherapy. Our data show that CCR1-expressing myeloid cells promote pancreatic cancer growth through modulation of the immune microenvironment and fibroblasts, indicating that CCR1 might be a suitable target for combination therapy.

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of

Author Info: (1) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (2) University of Michigan-Ann Arbor Ann Arbor, MI United States. (3) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (4) University of Michigan Medical Schooligan United States. (5) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (6) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (7) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (8) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (9) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (10) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (11) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (12) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (13) University of Maryland, Baltimore Baltimore United States. ROR: https://ror.org/04rq5mt64 (14) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (15) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (16) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (17) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (18) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (19) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (20) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (21) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (22) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (23) University of Michigan-Ann Arbor Ann Arbor United States. ROR: https://ror.org/00jmfr291 (24) University of Michigan-Ann Arbor United States. ROR: https://ror.org/00jmfr291 (25) Cornell University Ithaca United States. ROR: https://ror.org/05bnh6r87 (26) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (27) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (28) University of Michigan-Ann Arbor Ann Arbor, Michigan United States. ROR: https://ror.org/00jmfr291 (29) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (30) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (31) Cedars-Sinai Medical Center Los Angeles, CA United States. ROR: https://ror.org/02pammg90 (32) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291 (33) University of Michigan-Ann Arbor Ann Arbor, MI United States. ROR: https://ror.org/00jmfr291

Citation: Cancer Immunol Res 2026 May 28 Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42207977

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Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial Spotlight 

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

ABSTRACT: Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (5) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (6) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (7) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (8) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (9) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (10) Department of Genitourinary Oncology, Weill Cornell Medicine, New York, NY, USA. (11) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (12) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (13) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (14) Immune Monitoring Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (15) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (16) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (17) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (18) Department of Pharmacy, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (19) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (20) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (21) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (22) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (23) USF Health Morsani College of Medicine, Tampa, FL, USA. Tampa General Hospital Cancer Institute, Tampa, FL, USA. (24) Department of Genitourinary Oncology, Orlando Health Cancer Institute, Orlando, FL, USA. Jad.Chahoud@orlandohealth.com.

Citation: Nat Commun 2026 May 25 Epub05/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42185255

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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

    Tags:

    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:
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