The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity.
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| Title: | The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity. |
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| Authors: | Zhang, Xixi (AUTHOR), Xirenayi, Sherin (AUTHOR), Zhao, Ye (AUTHOR), Wang, Wen (AUTHOR), Han, Yuyang (AUTHOR), Sobral, Miguel (AUTHOR), Kang, Shawn (AUTHOR), Zhang, Chi (AUTHOR), Barlow, Graham L. (AUTHOR), Pyrdol, Jason (AUTHOR), Cho, Jae-Won (AUTHOR), Huang, Kun (AUTHOR), Ning, Xiaohan (AUTHOR), Hemberg, Martin (AUTHOR), Yuan, Guo-Cheng (AUTHOR), Van Allen, Eliezer M. (AUTHOR), Mooney, David J. (AUTHOR), Wucherpfennig, Kai W. (AUTHOR) |
| Source: | Science. 7/9/2026, Vol. 393 Issue 6807, p1-21. 21p. |
| Subjects: | Dendritic cells, Antigen presentation, Immune response, Protein arginine methyltransferases, Epigenetics, Immunotherapy, T cells, Tumor microenvironment |
| 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. Editor's summary: Dendritic cells (DCs) are essential for cancer immunity because they prime tumor-specific T cells. Therefore, a pharmacological strategy to selectively enhance DC function could be desirable as a cancer immunotherapy. Zhang et al. report that therapeutic targeting of the epigenetic enzyme CARM1 improves the ability of DCs to activate tumor-specific T cells, resulting in enhanced tumor immunity. DCs can switch from tolerogenic to immune-stimulatory states, and CARM1 inhibition increases the chromatin accessibility of key transcription factors involved in DC activation. CARM1 integrates input from multiple cytokine receptors to epigenetically regulate DC function, including the immunosuppressive cytokine transforming growth factor-β, which directly regulates CARM1 expression. Local delivery of a small-molecule CARM1 inhibitor with a neoantigen-targeting cancer vaccine enhanced vaccine efficacy and expansion of neoantigen-specific T cells. —Priscilla N. Kelly INTRODUCTION: Protective cancer immunity requires cooperative action by two major immune cell populations: dendritic cells (DCs) and T cells. DCs present antigens from apoptotic cancer cells to T cells, enabling T cell activation and infiltration into tumors. Although great advances have been made to enhance the function of T cells in the cancer-immunity cycle, strategies for effective therapeutic targeting of tumor-infiltrating DCs remain to be developed. Of particular interest are cDC1s (type I conventional DCs), a DC subpopulation with the distinctive ability to "cross-present" antigens from apoptotic tumor cells to CD8 T cells that serve as cytotoxic effector cells in tumor immunity. RATIONALE: DCs can shift from tolerogenic to highly immunostimulatory states in response to signals from cytokines and pattern-recognition receptors. We investigated the role of the CARM1 (coactivator-associated arginine methyltransferase 1) epigenetic enzyme in cDC1s, which acts as a transcriptional co-activator for several transcription factors by methylating arginine resides of chromatin-associated proteins. CARM1 was previously shown to play a cancer cell–intrinsic role by acting as a transcriptional co-activator of oncogenic transcription factors, including c-Myc. RESULTS: We discovered that inactivation of the Carm1 gene in cDC1 enhanced their ability to cross-present antigens from apoptotic cancer cells to CD8 T cells, resulting in enhanced T cell activation and proliferation. Conditional inactivation of Carm1 in cDC1 increased tumor infiltration by activated, cytotoxic effector T cells and sensitized resistant cancer cells to PD-1 (programmed cell death 1) inhibition. However, Carm1 inactivation in cDC1 had no detectable effect on steady-state cDC1 in healthy mice. Tumor-infiltrating Carm1-deficient cDC1 overexpressed many genes related to cDC1 activation, including genes in the major histocompatibility complex (MHC) antigen presentation, costimulation, and nuclear factor κB (NF-kB) pathways. At the epigenetic level, Carm1-deficient cDC1 showed greater chromatin accessibility for BATF3 and RelA (NF-κB) transcription factor motifs. Transcriptional changes were only observed in cDC1 but not the related cDC2 population, potentially because the BATF3 transcription factor is essential for cDC1 but not cDC2 function. Mechanistic studies demonstrated that CARM1 mRNA levels in cDC1 were regulated by cytokines relevant in the tumor microenvironment: transforming growth factor–β (TGFβ) (inhibitory) increased CARM1 mRNA levels, whereas type 1 interferons and tumor necrosis factor–α (TNFα) (stimulatory) inhibited CARM1 expression. CARM1 thus integrated multiple cytokine signals to regulate the epigenetic program of cDC1. Local delivery of a small-molecule CARM1 inhibitor with a neoantigen-based cancer vaccine enhanced cDC1 recruitment and expansion of neoantigen-specific T cells, resulting in more durable tumor control. This pathway was also conserved in human cDC1 differentiated from hematopoietic stem cells. In human cDC1, inactivation of the CARM1 gene or treatment with a small-molecule inhibitor enhanced expression of MHC-I [human lymphocyte antigen (HLA)–ABC] and MHC-II (HLA-DR) proteins and costimulatory molecules. Human CARM1-deficient cDC1 more efficiently cross-presented an endogenous tumor antigen to CD8 T cells. CONCLUSION: CARM1 acts as an important epigenetic regulator of cDC1 function in tumor immunity and integrates key cytokine signals from the tumor microenvironment. Small-molecule mediated targeting of CARM1 may enable selective enhancement of cDC1 function in the cancer-immunity cycle. Targeting of the CARM1 epigenetic enzyme enhances dendritic cell function in the cancer-immunity cycle.: (A) cDC1 function is impaired in tumors because of TGFβ-induced up-regulation of the CARM1 epigenetic enzyme. (B) CARM1 inhibition in cDC1s increases cDC1 infiltration into tumors, migration to tumor-draining lymph nodes, and cross-presentation of tumor antigens to CD8 T cells, resulting in enhanced tumor immunity. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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. Editor's summary: Dendritic cells (DCs) are essential for cancer immunity because they prime tumor-specific T cells. Therefore, a pharmacological strategy to selectively enhance DC function could be desirable as a cancer immunotherapy. Zhang et al. report that therapeutic targeting of the epigenetic enzyme CARM1 improves the ability of DCs to activate tumor-specific T cells, resulting in enhanced tumor immunity. DCs can switch from tolerogenic to immune-stimulatory states, and CARM1 inhibition increases the chromatin accessibility of key transcription factors involved in DC activation. CARM1 integrates input from multiple cytokine receptors to epigenetically regulate DC function, including the immunosuppressive cytokine transforming growth factor-β, which directly regulates CARM1 expression. Local delivery of a small-molecule CARM1 inhibitor with a neoantigen-targeting cancer vaccine enhanced vaccine efficacy and expansion of neoantigen-specific T cells. —Priscilla N. Kelly INTRODUCTION: Protective cancer immunity requires cooperative action by two major immune cell populations: dendritic cells (DCs) and T cells. DCs present antigens from apoptotic cancer cells to T cells, enabling T cell activation and infiltration into tumors. Although great advances have been made to enhance the function of T cells in the cancer-immunity cycle, strategies for effective therapeutic targeting of tumor-infiltrating DCs remain to be developed. Of particular interest are cDC1s (type I conventional DCs), a DC subpopulation with the distinctive ability to "cross-present" antigens from apoptotic tumor cells to CD8 T cells that serve as cytotoxic effector cells in tumor immunity. RATIONALE: DCs can shift from tolerogenic to highly immunostimulatory states in response to signals from cytokines and pattern-recognition receptors. We investigated the role of the CARM1 (coactivator-associated arginine methyltransferase 1) epigenetic enzyme in cDC1s, which acts as a transcriptional co-activator for several transcription factors by methylating arginine resides of chromatin-associated proteins. CARM1 was previously shown to play a cancer cell–intrinsic role by acting as a transcriptional co-activator of oncogenic transcription factors, including c-Myc. RESULTS: We discovered that inactivation of the Carm1 gene in cDC1 enhanced their ability to cross-present antigens from apoptotic cancer cells to CD8 T cells, resulting in enhanced T cell activation and proliferation. Conditional inactivation of Carm1 in cDC1 increased tumor infiltration by activated, cytotoxic effector T cells and sensitized resistant cancer cells to PD-1 (programmed cell death 1) inhibition. However, Carm1 inactivation in cDC1 had no detectable effect on steady-state cDC1 in healthy mice. Tumor-infiltrating Carm1-deficient cDC1 overexpressed many genes related to cDC1 activation, including genes in the major histocompatibility complex (MHC) antigen presentation, costimulation, and nuclear factor κB (NF-kB) pathways. At the epigenetic level, Carm1-deficient cDC1 showed greater chromatin accessibility for BATF3 and RelA (NF-κB) transcription factor motifs. Transcriptional changes were only observed in cDC1 but not the related cDC2 population, potentially because the BATF3 transcription factor is essential for cDC1 but not cDC2 function. Mechanistic studies demonstrated that CARM1 mRNA levels in cDC1 were regulated by cytokines relevant in the tumor microenvironment: transforming growth factor–β (TGFβ) (inhibitory) increased CARM1 mRNA levels, whereas type 1 interferons and tumor necrosis factor–α (TNFα) (stimulatory) inhibited CARM1 expression. CARM1 thus integrated multiple cytokine signals to regulate the epigenetic program of cDC1. Local delivery of a small-molecule CARM1 inhibitor with a neoantigen-based cancer vaccine enhanced cDC1 recruitment and expansion of neoantigen-specific T cells, resulting in more durable tumor control. This pathway was also conserved in human cDC1 differentiated from hematopoietic stem cells. In human cDC1, inactivation of the CARM1 gene or treatment with a small-molecule inhibitor enhanced expression of MHC-I [human lymphocyte antigen (HLA)–ABC] and MHC-II (HLA-DR) proteins and costimulatory molecules. Human CARM1-deficient cDC1 more efficiently cross-presented an endogenous tumor antigen to CD8 T cells. CONCLUSION: CARM1 acts as an important epigenetic regulator of cDC1 function in tumor immunity and integrates key cytokine signals from the tumor microenvironment. Small-molecule mediated targeting of CARM1 may enable selective enhancement of cDC1 function in the cancer-immunity cycle. Targeting of the CARM1 epigenetic enzyme enhances dendritic cell function in the cancer-immunity cycle.: (A) cDC1 function is impaired in tumors because of TGFβ-induced up-regulation of the CARM1 epigenetic enzyme. (B) CARM1 inhibition in cDC1s increases cDC1 infiltration into tumors, migration to tumor-draining lymph nodes, and cross-presentation of tumor antigens to CD8 T cells, resulting in enhanced tumor immunity. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aea1200 |
