PO.CL05.10 · 临床研究

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

海报缩略图：Ovarian tumor FAK inhibition releases omega-3 fatty acids stimulating GATA6 peritoneal macrophage CXCL13 production augmenting TIGIT immunotherapy

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

分会场 Tumor Microenvironment Modulators

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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

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.

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