PO.TB10.11 · 肿瘤生物学

小鼠胰腺肿瘤中的抗原呈递型癌症相关成纤维细胞通过 CCL22 差异性地调控调节性 T 细胞的表型与功能

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 Authors & Affiliations

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

中文摘要

胰腺导管腺癌（PDAC）以免疫抑制性肿瘤微环境（TME）为特征，其中癌症相关成纤维细胞（CAFs）在塑造治疗反应中发挥关键作用。在这些细胞中，表达 MHC-II 的抗原呈递型 CAFs（apCAFs）可调控 CD4 T 细胞活性，但其对抗肿瘤免疫反应的贡献仍不明确。利用对免疫检查点阻断（ICB）敏感性不同的 KPC 小鼠 PDAC 模型肿瘤克隆，我们发现免疫敏感型（sKPC）肿瘤比耐药型（rKPC）肿瘤表现出更高的 apCAF 浸润。在 sKPC 肿瘤中清除 apCAFs 会损害对 ICB 的反应性，突显了其在介导有效抗肿瘤免疫中的作用。离体实验表明，来自两种模型的 apCAFs 均可激活 CD4 T 细胞并诱导调节性 T 细胞（Treg）分化。然而，单细胞转录组学揭示，rKPC apCAFs 会促使 Tregs 具有更强的免疫抑制特征，这由不同的趋化因子信号驱动。值得注意的是，我们鉴定出 rKPC 来源的 apCAFs 中 CCL22 表达和信号升高，是增强 Treg 介导抑制的一个促成因素。功能性阻断 CCL22 降低了 rKPC apCAF 诱导的 Tregs 的 TGFbeta 分泌，支持该通路在促成免疫抑制性 TME 中的机制作用。这些发现将 apCAFs 定位为 PDAC 中 CD4 T 细胞抗肿瘤免疫的调节因子，并提示调控 apCAF-T 细胞相互作用可能提供增强免疫治疗疗效的策略。

查看英文原文 English 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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