Project description:Pancreatic ductal adenocarcinoma (PDAC) displays a poor response to immunotherapy. This poor response is predominantly attributed to the highly immunosuppressive tumor microenvironment (TME), characterized by a scarcity and dysfunction of infiltrating CD8+ T cells. Epigenetic regulators have recently been implicated in immune escape and immunotherapy sensitivity, presenting an appealing approach for directly targeting epigenetic factors or combining epigenetic therapies with immunotherapy in PDAC. Our study is the first to delineate the regulatory function of the epigenetic factor Sin3B in the tumor immune microenvironment (TIME) of PDAC. Using murine PDAC models, we discovered that intrinsic Sin3B loss in tumor cells reshapes the TIME, manifested by increased CD8+ T cell infiltration into tumors through enhanced secretion of CXCL9 and CXCL10. This was accompanied by an increase in the cytotoxicity of CD8+ T cells, as evidenced by elevated Granzyme B (GzmB) and IFNγ production. Furthermore, Sin3B-deficient tumor cells exhibited heightened secretion of CXCL9/10 in response to IFNγ, creating a positive feedback loop via the CXCL9/10-CXCR3 axis and thus intensifying immune response against PDAC. Additionally, loss of Sin3B increased PDAC susceptibility to anti-PD1 therapy in mice. Corroborating our findings in the mouse model, analysis of human PDAC samples demonstrated a significant inverse correlation between Sin3B levels and both CD8+ T cell presence and CXCL9/10 expression. Notably, PDAC patients with lower Sin3B expression exhibited a more favorable response to anti-PD1 therapy. Concerning the mechanism, we systematically uncovered the extensive epigenetic regulation employed by Sin3B loss via the modulation of H3K27Ac redistribution in PDAC cells. Sin3B deficiency resulted in an uptick of H3K27Ac peaks concentrated in the promoter and enhancer regions. Under the treatment of IFNγ, Sin3B loss leads to the enrichment of H3K27Ac peaks in promoter regions of ISG-related genes such as CXCL9 and CXCL10, thereby boosting their expression. Collectively, our research outcomes propose a potential target for enhancing the accessibility of cytotoxic T cells to the tumor site and improving immunotherapy in the challenging landscape of PDAC.

Project description:The direct and indirect effects of targeting specific tumor-associated macrophage (TAM) subsets in cancer are not well-defined. TAM targeting strategies are frequently based on the ‘M1’ or ‘M2’ polarization categories, even as substantial data challenges this binary modeling of macrophage cell state. One molecule consistently referenced as a delineator of a putative immunosuppressive ‘M2’ state is the surface protein CD206. We thus made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs and assess their correspondence with pro-tumoral immunity. Early, but not late depletion of CD206+ macrophages and monocytes (here, ‘Mono/Macs’) led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, and able to differentially attract activated CD8 T cells. In contrast, a population of stress-responsive TAMs (“Hypoxic” or Spp1+) and immature monocytes, which lack CD206 expression and become prominent following early depletion, expressed markedly diminished levels of CXCL9. Those NK and CD8 T cells which enter CD206-depleted tumors express vastly reduced levels of the corresponding receptor Cxcr3, the cDC1-attracting chemokine Xcl1 and cDC1 growth factor Flt3l transcripts. Consistent with the loss of this critical network, early CD206+ TAM depletion decreased tumor control by antigen specific CD8 T cells in mice. Likewise, in humans, the CD206Replete, but not the CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, NK cell and stimulatory cDC1 gene signatures and transcriptomic signatures skewed towards CD206Replete Mono/Macs associated with better survival. Together, these findings negate the unqualified classification of CD206+ ‘M2-like’ macrophages as immunosuppressive and provide further evidence of the context-dependence of macrophage function in tumors.

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VISTA Drives Pancreatic Tumor Progression Through Modulation of The Tumor-Associated Macrophage Polarity

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