Journal Articles

The efficacy of immunotherapy in glioma requires distal B cell responses in tumor-draining lymph nodes

Kim et al. showed that anti-CTLA-4 efficacy in orthotopic murine glioblastoma (GBM) models was abolished by B cell deficiency and tdLN removal. In WT mice, anti-CTLA-4 increased B cell numbers and GC reactions in tdLNs, but not in the TIME, and therapeutic efficacy required CD4+ T cell help to B cells. While maintaining tumor-reactive CD4+ T cell function in the TIME, in tdLNs, anti-CTLA-4 therapy boosted TFH cell differentiation to support GC B cell clonal expansion and generation of antibody-secreting cells producing tumor-binding class-switched IgG1 antibodies that promoted macrophage-mediated phagocytosis of glioma cells via Fc receptor signaling.

Contributed by Paula Hochman

Kim et al. showed that anti-CTLA-4 efficacy in orthotopic murine glioblastoma (GBM) models was abolished by B cell deficiency and tdLN removal. In WT mice, anti-CTLA-4 increased B cell numbers and GC reactions in tdLNs, but not in the TIME, and therapeutic efficacy required CD4+ T cell help to B cells. While maintaining tumor-reactive CD4+ T cell function in the TIME, in tdLNs, anti-CTLA-4 therapy boosted TFH cell differentiation to support GC B cell clonal expansion and generation of antibody-secreting cells producing tumor-binding class-switched IgG1 antibodies that promoted macrophage-mediated phagocytosis of glioma cells via Fc receptor signaling.

Contributed by Paula Hochman

ABSTRACT: Humoral immunity, mediated by B cells that mature in germinal centers in lymph nodes (LNs), is essential for adaptive immune responses, but its role in antitumor immunity and responses to immunotherapy remain unclear. Here, we show that activation of B cells in tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 (cytotoxic T lymphocyte-associated protein 4) immune checkpoint blockade in glioma in vivo. Anti-CTLA-4 therapy enhanced T follicular helper cell (T(FH) cell) expansion in dcLNs, leading to germinal center B cell responses, immunoglobulin G (IgG) class switching, and the generation of glioma-reactive antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Distally secreted IgG accumulated in the tumor microenvironment and promoted glioma cell phagocytosis in vivo. These findings define a B cell-dependent mechanism underlying CTLA-4-mediated control of glioma and provide a conceptual framework for future therapeutic strategies in tumor.

Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host D

Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (3) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (4) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (5) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (6) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (7) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (8) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (9) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (10) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (11) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (12) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Department of Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. (13) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (14) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (15) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Regenerative Medical Research Institute (reMRI) for Aging-Related Diseases, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

mRNA lipid nanoparticle cancer vaccine platform delivering multiple STING activators for enhanced antitumor activity

Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.

Contributed by Paula Hochman

Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.

Contributed by Paula Hochman

ABSTRACT: mRNA-based cancer vaccines offer a modular and safe platform to elicit antitumor immunity, yet their efficacy is often limited by inefficient mRNA delivery and inadequate dendritic cell (DC) activation, both of which are essential for initiating robust cytotoxic T cell responses. Inadequate innate immune activation coupled with poor antigen presentation further diminishes their effectiveness, particularly in immunologically "cold" tumors. While stimulator of interferon genes (STING) agonists can enhance DC maturation and cross-presentation, their therapeutic utility is constrained by poor intracellular delivery and limited colocalization with tumor antigens. In this study, we developed a lipid nanoparticle (LNP) platform via high-throughput screening of ionizable lipids for potent mRNA delivery to DCs both in vitro and in vivo. To amplify immune activation, we coencapsulated the STING agonists c-di-AMP (AMP) and manganese (Mn(2+)) together with tumor antigen-encoding mRNA into the lead LNP formulation. This codelivery strategy synergistically activated type I interferon signaling, upregulated costimulatory molecules, enhanced antigen presentation, and elicited potent tumor-specific T cell responses and superior antitumor efficacy. Our results demonstrate that integrating innate immune stimulation with mRNA-LNP delivery provides a promising strategy to overcome current limitations in mRNA vaccine efficacy and to improve cancer immunotherapy outcomes.

Author Info: (1) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (2) Department of Bioengineering, University of Pennsylvania, P

Author Info: (1) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (2) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (3) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (4) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (5) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (6) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (7) Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, China. ROR: https://ror.org/04f49ff35 (8) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (9) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (10) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (11) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (12) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (13) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (14) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (15) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Republic of Singapore, Singapore 138668, Singapore. ROR: https://ror.org/036wvzt09 (16) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (17) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (18) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (19) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (20) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (21) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10

Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells

Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.

Contributed by Lauren Hitchings

Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.

Contributed by Lauren Hitchings

ABSTRACT: Type 1 regulatory T (Tr1) cells are CD4(+) T cells with suppressive function that are induced from conventional T cells exposed to persistent or strong antigens. Human Tr1 cells are understudied; the regulators of their antigen-driven differentiation are unknown, and identifying them in tissues, where antigen interactions occur, is challenging. Here, we conducted a multiomic profiling of human antigen-induced Tr1 cells. Using CRISPR-based functional genomics, we uncovered essential roles of transcription factors IRF4, BATF, and MAF in human Tr1 differentiation, phenotype, and function. We also derived a Tr1 transcriptional signature that detects cells with a Tr1 phenotype in single-cell datasets from patients treated with Tr1 therapy and those with solid tumors. Cross-species analysis confirmed this signature identifies bona fide Tr1 cells induced in vivo in a murine solid tumor model. These findings provide a framework for development of Tr1-based and Tr1-targeting therapies and studies of Tr1 cell biology.

Author Info: (1) Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Division of Hematology, Oncology, Stem Cell Transplantation and R

Author Info: (1) Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. (3) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (4) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (5) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (6) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (7) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (8) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (9) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Immunology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. (10) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (12) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (13) Integrative Cellular Biology and Bioinformatics, Saarland University, SaarbrŸcken, Germany. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (14) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (15) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. (16) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity

Zhang et al. investigated the role of the CARM1 in cDC1s and found that while its effect on cDC1s in healthy tissues was minimal, inactivation of Carm1 in tumor cDC1s enhanced their activation and cross-presentation of tumor antigens, resulting in increased CD8+ T cell-mediated antitumor efficacy. Carm1 expression was found to be downregulated by type 1 IFN and TNFα, and upregulated by TGFβ via Smad2/3. CARM1 altered chromatin expression, with its loss leading to enhanced chromatin access at regions associated with NF-κB and AP-1 binding, which supported enhanced activation and antigen presentation. When used in combination with a neoantigen vaccine, inhibition of Carm1 enhanced antitumor responses.

Zhang et al. investigated the role of the CARM1 in cDC1s and found that while its effect on cDC1s in healthy tissues was minimal, inactivation of Carm1 in tumor cDC1s enhanced their activation and cross-presentation of tumor antigens, resulting in increased CD8+ T cell-mediated antitumor efficacy. Carm1 expression was found to be downregulated by type 1 IFN and TNFα, and upregulated by TGFβ via Smad2/3. CARM1 altered chromatin expression, with its loss leading to enhanced chromatin access at regions associated with NF-κB and AP-1 binding, which supported enhanced activation and antigen presentation. When used in combination with a neoantigen vaccine, inhibition of Carm1 enhanced antitumor responses.

ABSTRACT: The cancer-immunity cycle requires cross-presenting type I conventional dendritic cells (cDC1s) that induce T cell-mediated immunity, but therapeutic strategies for enhancing intratumoral cDC1 function are currently inadequate. We found the epigenetic enzyme CARM1 (coactivator-associated arginine methyltransferase 1) to be a selective negative regulator of cancer antigen presentation by cDC1s but not cDC2s. Inactivation of the Carm1 gene promoted cDC1 antigen cross-presentation, activation, and accumulation in tumors, and a CARM1 inhibitor enhanced cDC1-mediated priming of T cells by means of a cancer neoantigen vaccine. CARM1 inhibition increased chromatin accessibility at BATF3-Jun and RelA sites that are critical for cDC1 function and activation. Transforming growth factor-β regulated Carm1 expression, which suggests that CARM1 inactivation enhanced intratumoral cDC1 function without altering cDC1 homeostasis. These studies identify CARM1 as a potential therapeutic target for enhancing the antitumor function of mouse and human cDC1s.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department o

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. Systems, Synthetic, and Quantitative Biology Graduate Program, Harvard University, Cambridge, MA, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (6) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. (7) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (12) Molecular Imaging Core, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (14) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (15) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Black Family Stem Cell Institute, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity

Spotlight 

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

ABSTRACT: Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFN-γ suppresses the expression of System Xc-, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1-specific TCR-T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2 microglobulin knockout counterparts. In NOG mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape variant tumor clones, offering a promising strategy for cancer treatment.

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (4) Aichi Cancer Center Research Institute Chikusa-ku, Nagoya, Aichi Japan. (5) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (6) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (7) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (8) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (9) Takara Bio Inc. Kusatsu, Shiga Japan. (10) Takara Bio Inc. Otsu, Shiga Japan. (11) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (12) Nagasaki University Nagasaki, Nagasaki Japan. ROR: https://ror.org/058h74p94

Single-cell transcriptomic analysis reveals tumor-immune determinants of lymph node colonization and progression in thyroid cancer Spotlight 

Nguyen et al. used single-cell RNAseq and multiplex IHC on paired primary thyroid carcinomas and metastatic lymph nodes (LNs) to define immune determinants of nodal colonization. In metastatic LNs, thyrocytes and TAMs downregulated inflammatory cytokine receptors. including TNFRSF12A and CX3CR1, and were enriched for Tregs relative to matched primary tumors, which suggests suppression of T cell-mediated cytotoxicity. Tumor-infiltrating lymphocytes in metastatic LNs showed increased IL7R expression, and high IL7R levels within nodal metastases correlated with enhanced immune activation and improved progression-free survival in a validation cohort.

Contributed by Shishir Pant

Nguyen et al. used single-cell RNAseq and multiplex IHC on paired primary thyroid carcinomas and metastatic lymph nodes (LNs) to define immune determinants of nodal colonization. In metastatic LNs, thyrocytes and TAMs downregulated inflammatory cytokine receptors. including TNFRSF12A and CX3CR1, and were enriched for Tregs relative to matched primary tumors, which suggests suppression of T cell-mediated cytotoxicity. Tumor-infiltrating lymphocytes in metastatic LNs showed increased IL7R expression, and high IL7R levels within nodal metastases correlated with enhanced immune activation and improved progression-free survival in a validation cohort.

Contributed by Shishir Pant

ABSTRACT: Lymph node (LN) metastases are a major driver of mortality across solid cancers, including thyroid carcinomas, which are known for high rates of nodal colonization. To elucidate the determinants of nodal spread, we isolated tumor-infiltrating leukocytes from primary thyroid tumors and matched metastatic LNs for single-cell RNA sequencing with validation by multiplex immunohistochemistry. Comparing the microenvironmental alterations between primary tumors and their LNs, we found that thyrocytes and tumor-associated macrophages down-regulate the expression of multiple inflammatory cytokine receptors, including TNFRSF12A and CX3CR1, upon LN colonization. LNs were associated with the induction of regulatory T cells to suppress T cell-mediated cytotoxicity compared to matched primary tumors. Notably, tumor-infiltrating lymphocytes within LNs demonstrated increased expression of activation markers, including interleukin-7 receptor (IL7R). High LN expression of IL7R was significantly correlated with improved outcomes and can serve as a biomarker in this heterogeneous disease. Our findings on the dynamic equilibrium within LN metastases may offer conserved mechanisms for nodal colonization across solid tumors.

Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA,

Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (2) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (3) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (4) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (5) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (6) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (7) Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (8) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (9) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (10) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (11) Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (12) Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (13) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (14) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (15) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (16) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (17) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (18) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Sustained A2AR expression and loss paradoxically promote CD8+ T cell exhaustion

Spotlight 

Using single-cell multiomics and genetic models, Song and Kharel et al. showed that, paradoxically, both sustained A2AR expression under chronic antigen exposure and hypoxia, and complete loss of A2AR drive the transition of TCFhi memory-like progenitor (Tpro) cells to exhausted T cells. A2AR expression was rapidly induced upon TCR stimulation and was required to sustain CD8+ T cell functions. Persistent A2AR expression promoted continuous TCR engagement and CD8+ T cell exhaustion via activation of the GαS-cAMP-PKA pathway. A2AR depletion led to epigenetic remodeling and activation of CD122 (IL-2Rβ)-dependent signaling, driving exhaustion.

Contributed by Ute Burkhardt

Using single-cell multiomics and genetic models, Song and Kharel et al. showed that, paradoxically, both sustained A2AR expression under chronic antigen exposure and hypoxia, and complete loss of A2AR drive the transition of TCFhi memory-like progenitor (Tpro) cells to exhausted T cells. A2AR expression was rapidly induced upon TCR stimulation and was required to sustain CD8+ T cell functions. Persistent A2AR expression promoted continuous TCR engagement and CD8+ T cell exhaustion via activation of the GαS-cAMP-PKA pathway. A2AR depletion led to epigenetic remodeling and activation of CD122 (IL-2Rβ)-dependent signaling, driving exhaustion.

Contributed by Ute Burkhardt

ABSTRACT: Although A2AR is a key immunoregulatory receptor that suppresses CD8(+) T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8(+) T cell differentiation and cell-fate decisions during chronic viral infection and cancer remains poorly understood. Using A2AR-eGFP reporter mice, we show that A2AR expression is rapidly induced by TCR stimulation and persists under chronic antigen exposure and hypoxia, with sustained expression strongly associated with terminal exhaustion via the canonical G_(s)-cAMP-PKA pathway. Paradoxically, A2AR loss does not alleviate exhaustion but instead accelerates differentiation toward the terminally exhausted state. Single-cell multiomics profiling revealed that A2AR deficiency activates CD122 (IL-2R_)-dependent signaling, driving T cell exhaustion. Genetic deletion of CD122 in A2AR-deficient CD8(+) T cells reduced terminal exhaustion, identifying CD122 signaling as a key mediator of A2AR loss-driven exhaustion. Intriguingly, both sustained A2AR expression and A2AR loss converge to promote T cell exhaustion differentiation through distinct mechanisms. These findings uncover a paradoxical role of A2AR in shaping CD8(+) T cell fate choices during chronic infection and cancer.

Author Info: (1) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611.

Author Info: (1) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (2) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (3) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (4) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (5) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (6) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (7) Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. ROR: https://ror.org/056swr059 (8) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (9) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57

RIG-I-targeted immunotherapy synergizes with immune checkpoint inhibition in a hepatocellular carcinoma model Spotlight 

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

ABSTRACT: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic pattern recognition receptor that senses short double-stranded RNA with uncapped 5'-triphosphate (3p-RNA). Upon activation, RIG-I induces type I interferons and proinflammatory cytokines, thereby promoting adaptive immunity. Thus, RIG-I activation is a promising approach for creating a proinflammatory tumor microenvironment. In this study, we investigated its therapeutic potential in hepatocellular carcinoma (HCC). We explored and confirmed RIG-I expression and signaling in human HCC samples and cell lines. The therapeutic potential of RIG-I activation by 3p-RNA for the treatment of HCC was investigated in vitro and in syngeneic murine orthotopic tumor models. In vivo, 3p-RNA treatment significantly reduced the tumor burden, delayed disease progression, and achieved partial complete remission of RIL-175 tumors with durable immune memory. However, no therapeutic effects were observed in the Hep-55.1C model. Tumor clearance depended on CD4⁺ and CD8⁺ T cells, but not NK cells. Additionally, 3p-RNA induced PD-L1 expression on HCC cells, enhancing their sensitivity to anti-PD-1 immune checkpoint therapy in vivo. RIG-I activation via 3p-RNA therapy shows promise as an immunotherapeutic strategy for hepatocellular carcinoma (HCC). Future investigations need to focus on tumor-intrinsic factors to understand heterogeneity between tumors and to overcome resistance mechanisms.

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.or

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (4) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (5) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (6) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (7) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (8) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (9) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (10) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (11) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (12) Ludwig-Maximilians-UniversitŠt MŸnchen Munich, Bavaria Germany. ROR: https://ror.org/05591te55 (13) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (14) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (15) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (16) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (17) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (18) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (19) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (20) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32

FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer Spotlight 

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

BACKGROUND: Non-small cell lung cancer (NSCLC) frequently evades immune surveillance through defective antigen presentation and a suppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint blockade (ICB). Conventional type 1 dendritic cells (cDC1s) are essential for initiating antitumor CD8(+) T-cell responses; however, their abundance and function are often diminished in NSCLC, contributing to poor outcomes and resistance to immunotherapy. We hypothesized that in situ vaccination (ISV) using gene-modified cDC1s engineered to secrete FMS-like tyrosine kinase 3 ligand (FLT3L) would enhance cDC1 function within the TME, promote antitumor immunity, and improve responses to ICB. METHODS: Syngeneic murine models of NSCLC (Kras(G12D)/P53(-/-)/Lkb1(-/-); Kras(G12D)/P53(-/-) ; and Kras(G12D) ) with varying tumor mutational burden, along with the MC38 model, were used to assess the therapeutic efficacy of FLT3L-cDC1 ISV. Flow cytometry and multiplex immunofluorescence were used to evaluate immune mechanisms of response. To assess translational relevance, immune and tertiary lymphoid structure (TLS) signatures were analyzed in The Cancer Genome Atlas (TCGA) NSCLC datasets, with TLS signatures refined using a retrained xCell2 framework incorporating curated TLS and high endothelial venule (HEV) microdissection datasets. RESULTS: FLT3L-cDC1 ISV remodeled the TME across multiple NSCLC models, inducing T lymphocyte infiltration and expanding cytolytic CD8(+) T cells. FLT3L-cDC1 ISV was associated with increased formation of immature TLS with primary follicle-like features within the TME. TCGA analyses revealed that FLT3L expression correlates with activated DC, T cell, and B cell signatures, as well as HEV-enriched TLS-associated programs. Combination with PD-1 blockade further enhanced the antitumor immunity of FLT3L-cDC1 ISV, resulting in robust local and systemic T-cell activation and the expansion of activated CCR7(+)PD-L1(+) cDC1s and stem-like TCF1(+)PD-1(+) CD8(+) progenitors within the TME. In an LKB1-deficient NSCLC model, FLT3L-cDC1 ISV plus PD-1 blockade induced complete and durable regression in 85% of tumors, leading to long-lasting systemic tumor-specific immune memory, consistent with effective tumor vaccination. CONCLUSIONS: FLT3L-cDC1 ISV represents a rational cytokine-enhanced cellular immunotherapy designed to overcome immunosuppression and restore DC function within the TME, thereby promoting tumor-specific adaptive immune responses and enhancing responsiveness to ICB.

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (3) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (4) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (5) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (6) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (7) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (8) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (9) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (10) UCLA, Los Angeles, California, USA. (11) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (12) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (13) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (14) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (15) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (16) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. (17) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

B cell-derived type I interferon sustains T cell functionality upon strong TCR stimulation during chronic infection Spotlight 

Graça et al. show that B cells are essential for CD8+ T cell effector response during chronic, but not acute, LCMV infection. In chronic infection, splenic B cells sense viruses via TLR7/8-STING pathways and produce IFN-I, which promotes exhausted T cell differentiation and sustain effector function in the spleen, whereas CD8+ T cells in the LN or responding to low antigen load were B cell independent. Loss of B cells or IFN-I signaling impaired exhausted T cell cytokine production (‘tolerized-like’). IRF1 integrates IFN-I signals to promote T cell expansion. Chronic human HBV showed a similar antigen-load-dependent effect observed in the murine LCMV model.

Contributed by Shishir Pant

Graça et al. show that B cells are essential for CD8+ T cell effector response during chronic, but not acute, LCMV infection. In chronic infection, splenic B cells sense viruses via TLR7/8-STING pathways and produce IFN-I, which promotes exhausted T cell differentiation and sustain effector function in the spleen, whereas CD8+ T cells in the LN or responding to low antigen load were B cell independent. Loss of B cells or IFN-I signaling impaired exhausted T cell cytokine production (‘tolerized-like’). IRF1 integrates IFN-I signals to promote T cell expansion. Chronic human HBV showed a similar antigen-load-dependent effect observed in the murine LCMV model.

Contributed by Shishir Pant

ABSTRACT: B cells are highly abundant lymphocytes and central players in humoral immunity. Although T cells are well known to support humoral responses, how B cells influence T cell responses is less understood. Here, we show that B cells are critical for CD8(+) T cell responses to chronic, but not acute, viral infections. In the absence of B cells, T cells responding to chronic infection exhibited severely impaired effector differentiation. This dependency on B cell help was dictated by high antigen loads and strong T cell receptor (TCR) stimulation. Loss of either B cells or interferon-I (IFN-I) signaling led to severe functional deficits in exhausted T cells, implicating B cells as key producers of IFN-I. The IFN-I-dependent T cell response to strong TCR stimulation is mediated, in part, by the transcription factor IRF1. Therefore, during chronic infection, we uncover an important role for B cell-derived IFN-I in modulating T cell responses to strong TCR stimulation.

Author Info: (1) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (2) Department of Microbi

Author Info: (1) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (2) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (3) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (4) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (5) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia; Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (6) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (7) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (8) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (9) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (10) Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany. (11) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (12) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (13) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. (14) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. (15) Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany. (16) Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Medical Center, University of Freiburg, Baden-WŸrttemberg, Germany. (17) Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Medical Center, University of Freiburg, Baden-WŸrttemberg, Germany. (18) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (19) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. (20) Computational Sciences Initiative (CSI), the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (21) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. (22) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Electronic address: yannick.alexandre@unimelb.edu.au. (23) Department of Microbiology and Immunology, the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Electronic address: daniel.utzschneider@unimelb.edu.au.

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