PO.TB10.11 · 肿瘤生物学

Antigen-presenting cancer-associated fibroblasts in murine pancreatic tumors differentially control regulatory T cell phenotype and function via CCL22

编号 6036 展板 13 时间 4/21 02:00–05:00 区域 Section 25 主讲 Saumya Maru, MD;PhD

分会场 Fibroblasts as Architects of the Tumor Microenvironment

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作者与单位

Saumya Maru¹, Meredith Wetzel², Jacob Mitchell², Nicole Gross², Lalitya Andaloori³, Kathryn Howe³, Emma Kartalia⁴, Guanglan Mo³, James Leatherman⁴, Won Jin Ho², Elana Judith Fertig⁵, Luciane Tsukamoto Kagohara⁶, Edward J. Pearce⁴, Elizabeth M. Jaffee⁴

¹Fox Chase Cancer Center, Philadelphia, PA,²Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD,³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD,⁴Johns Hopkins University School of Medicine, Baltimore, MD,⁵University of Maryland School of Medicine, Baltimore, MD,⁶Johns Hopkins University, Baltimore, MD

摘要 Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) play pivotal roles in shaping therapeutic responses. Among these, MHC-II-expressing antigen-presenting CAFs (apCAFs) modulate CD4 T cell activity, yet their contribution to the antitumor immune response remains unclear. Using tumor clones of the KPC murine PDAC model differing in sensitivity to immune checkpoint blockade (ICB), we show that immunosensitive (sKPC) tumors exhibit greater apCAF infiltration than resistant (rKPC) tumors. Depletion of apCAFs in sKPC tumors impaired responsiveness to ICB, highlighting their role in mediating effective antitumor immunity. Ex vivo assays revealed that apCAFs from both models activate CD4 T cells and induce regulatory T cell (Treg) differentiation. However, single-cell transcriptomics revealed that rKPC apCAFs promote Tregs with heightened immunosuppressive signatures, driven by distinct chemokine signaling. Notably, we identified elevated CCL22 expression and signaling in rKPC-derived apCAFs as a contributor to enhanced Treg-mediated suppression. Functional blockade of CCL22 reduced TGFbeta secretion by rKPC apCAF-induced Tregs, supporting a mechanistic role for this pathway in fostering an immunosuppressive TME. These findings position apCAFs as regulators of CD4 T cell antitumor immunity in PDAC, and suggest that modulating apCAF-T cell interactions could offer strategies to enhance immunotherapy efficacy.

利益披露 Disclosure

S. Maru, None.. M. Wetzel, None.. J. Mitchell, None.. N. Gross, None.. L. Andaloori, None.. K. Howe, None.. E. Kartalia, None.. G. Mo, None.. J. Leatherman, None. W. Ho, Rodeo/Amgen Patent. Sanofi ). NeoTX ). Riboscience ). Exelixis Other, speaking and travel honoraria. Standard BioTools Other, speaking and travel honoraria. E. J. Fertig, Resistance Bio Other, SAB. Mestag Other, personal fees. Merck Other, personal fees. Roche/Genetech ). Abbvie ). E. J. Pearce, Remedy Plan Therapeutics Other, SAB. E. M. Jaffee, Abmeta Other. Adventris Other. Dragonfly Other, personal fees. Neuvogen Other, personal fees. CPRIT Other, personal fees. Surge Tx Other, personal fees. Mestag Other, personal fees. Medical Home Group Other, personal fees. HDTbio Other, personal fees. Lustgarten ). Genentech ). BMS ). NeoTx ). Break Through Cancer ).

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