PO.CL05.10 · 临床研究

卵巢肿瘤FAK抑制释放omega-3脂肪酸，刺激GATA6腹膜巨噬细胞产生CXCL13，增强TIGIT免疫治疗

Ovarian tumor FAK inhibition releases omega-3 fatty acids stimulating GATA6 peritoneal macrophage CXCL13 production augmenting TIGIT immunotherapy

编号 7951 展板 26 时间 4/22 09:00–12:00 区域 Section 49 主讲 David Schlaepfer, PhD

分会场 Tumor Microenvironment Modulators

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Xiao Lei Chen¹, Kevin M. Tharp², Marjaana Ojalill¹, Duygu Ozmadenci¹, Antonia Boyer¹, Terrance J. Hannen¹, Christine Lawson¹, Hyojae J. Lee¹, Marvin Xia¹, Elise Tahon¹, Yichi Zhang¹, Cray Minor², Safir U. Khan¹, Colin C. Anderson³, Travis Nemkov³, Michael Rose⁴, Monica V. Estrada⁴, Alfredo A. Molinolo⁴, Elias Warren⁴, Patrick Penalosa¹, Ramez N. Eskander¹, Michael T. McHale¹, Shizhen E. Wang⁴, Denise C. Connolly⁵, Kathleen M. Fisch⁴, Dwayne G. Stupack¹, David D. Schlaepfer¹

¹Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, Moores Cancer Center, La Jolla, CA,²Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA,³Anschutz Medical Campus, University of Colorado Denver, Aurora, CO,⁴University of California San Diego, Moores Cancer Center, La Jolla, CA,⁵Fox Chase Cancer Center, Philadelphia, PA

摘要 Abstract

中文摘要

高级别浆液性卵巢癌（HGSOC）是一种致命的妇科恶性肿瘤，其原因在于累积的治疗耐药。黏着斑激酶（FAK）表达在HGSOC中升高，在同基因卵巢肿瘤中抑制FAK活性（FAKi）可减少肿瘤负荷，同时腹膜巨噬细胞的CXCL13趋化因子表达升高。将FAKi与聚乙二醇化多柔比星化疗和抗TIGIT免疫检查点抗体相结合可抑制肿瘤并延长生存，伴随三级淋巴结构的形成。腹膜巨噬细胞GATA6失活在体内降低了CXCL13表达，增强了FAK敲除（KO）肿瘤的生长，并限制了腹水B细胞浸润。经FAKi处理或FAK-KO的条件培养基中含有富含omega-3脂肪酸的外泌体，可刺激巨噬细胞产生CXCL13。通过腹腔穿刺术分离，经FAKi处理的HGSOC肿瘤细胞或经二十碳五烯酸处理的纯化巨噬细胞触发了抗肿瘤巨噬细胞重编程和CXCL13表达。总之，我们的研究界定了FAK抑制后一条肿瘤脂质向巨噬细胞的信号传导联系，支持B细胞招募、存活以及抗TIGIT免疫治疗的增强。

查看英文原文 English abstract

High grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy due to accumulated therapy resistance. Focal adhesion kinase (FAK) expression is elevated in HGSOC, and inhibition of FAK activity (FAKi) in syngeneic ovarian tumors reduced tumor burden with elevated CXCL13 chemokine expression by peritoneal macrophages. Combining FAKi with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody repressed tumors and extended survival with tertiary lymphoid structure formation. Peritoneal macrophage GATA6 inactivation reduced CXCL13 expression in vivo , enhanced FAK knockout (KO) tumor growth, and limited ascites B cell infiltration. FAKi-treated or FAK-KO conditioned media contained exosomes enriched with omega-3 fatty acids that stimulated macrophage CXCL13 production. As isolated by paracentesis, FAKi-treated HGSOC tumor cells or purified macrophages treated with eicosapentaenoic acid triggered anti-tumor macrophage reprogramming and CXCL13 expression. Together, our studies define a tumor lipid to macrophage signaling linkage upon FAK inhibition supporting B cell recruitment, survival, and anti-TIGIT immunotherapy enhancement.

利益披露 Disclosure

X. Chen, None.. K. M. Tharp, None.. M. Ojalill, None.. D. Ozmadenci, None.. A. Boyer, None.. T. J. Hannen, None.. C. Lawson, None.. H. J. Lee, None.. M. Xia, None.. E. Tahon, None.. Y. Zhang, None.. C. Minor, None.. S. U. Khan, None.. C. C. Anderson, None.. T. Nemkov, None.. M. Rose, None.. M. V. Estrada, None.. A. A. Molinolo, None.. E. Warren, None.. P. Penalosa, None.. R. N. Eskander, None.. M. T. McHale, None.. S. E. Wang, None.. D. C. Connolly, None.. K. M. Fisch, None. D. G. Stupack, Amplia Pharmaceuticals Other, consultant. D. D. Schlaepfer, None.

← 返回 AACR 2026 检索