Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy

Abstract

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition. eTOC BlurbHigh-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet pointsO_LIGenetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration C_LIO_LITumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 C_LIO_LIFAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures C_LIO_LIOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13 C_LI