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:Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest human malignancies with poor prognosis and limited therapeutic success. Despite significant advancements in therapeutic strategies over recent decades, the development of effective treatments for pancreatic ductal adenocarcinoma (PDAC) remains a major challenge due to its complex tumor microenvironment (TME). The PDAC TME is characterized by tumor-infiltrating immune cells, immunosuppressive cells, and cancer-associated fibroblasts (CAFs). The immune components, particularly the myeloid cells, play a role in the tumor microenvironment (TME). The myeloid compartment of the TME comprises a functionally diverse compartment of the TME, capable of exerting both pro-tumorigenic and antitumor effects depending on their phenotypic state and microenvironmental cues. In this study, we leveraged single-nucleus multiomic sequencing (snRNA-seq and snATAC-seq) of human pancreatic ductal adenocarcinoma (PDAC) tumors to dissect the immune landscape, particularly the myeloid subsets, in patients who received neoadjuvant chemotherapy, stratified as responders or non-responders based on histopathological evaluation. Our integrative analysis revealed striking differences in myeloid cell composition and transcriptional states, with a notable enrichment of lipid-associated macrophages (LAMs) in chemotherapy responders. LAMs exhibited a transcriptional program enriched for lipid metabolism, phagocytosis, and inflammatory signaling. Pseudotime and chromatin accessibility analyses from the ATAC-Seq data positioned LAMs as terminally differentiated, metabolically reprogrammed macrophages, shaped by immune and environmental cues. ChromVAR analysis identified AP-1, C/EBP, and metabolic transcription factor motif enrichment in LAMs from responders, indicating active immunometabolic states associated with treatment efficacy. These findings implicate LAMs as potential biomarkers and effectors of chemotherapeutic response in PDAC, providing new insights into myeloid cell plasticity and therapeutic reprogramming in the TME.

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Driving tumor-associated macrophages to a CXCL9Hi/SPP1Low phenotype eliminates pancreatic cancer

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