Abstract 6158: Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy

Abstract

Abstract The failure of large number of patients to respond to cancer immunotherapy remains a formidable challenge. The immunosuppressive tumor microenvironment (TME) can hinder the capability of cytotoxic T cells to fight cancer. In this regard, cancer associated fibroblasts (CAFs) are among the most abundant stromal cells in TME responsible for immunosuppression. Therefore, reversal of the immunosuppressive phenotype of CAFs and is a major therapeutic goal. Cancer cells secrete exosomes and other factors to reprogram fibroblasts and induce their differentiation into pro-tumorigenic CAFs. Also, cancer cells maintain the activated fibroblast phenotype via triggering major signaling pathways e.g., TGFβ1, FGFR, or β-catenin pathways in the fibroblasts. Here, our goal was to maintain a normalized quiescent phenotype of fibroblasts to enhance the efficacy of immune checkpoint blockade. We demonstrated that a tumor-targeted EpCAM antibody modified shikonin/GW4869 combination liposomes synergistically reduces the biogenesis and release of exosomes from A549 lung cancer cells which significantly inhibits differentiation of MRC5 lung fibroblasts into CAFs. In parallel, we showed the efficacy of TAS-120/ICG-001 FGFR-Wnt/β-catenin inhibitor combination liposomes decorated with GPR77 and CD10 targeting antibodies to switch the acquired activated CAFs phenotype to a quiescent one. Co-administration of both liposomes in low drug doses significantly enhanced the infiltration of cytotoxic CD8+ T cells and improved the antitumor efficacy of αPD-L1 antibody in LLC syngeneic mice model of lung cancer. In conclusion, simultaneous blockage of the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling may constitute an outstanding immunotherapeutic modality. Citation Format: Ahmed Elzoghby, May Freag, Mostafa Mohammed, Krishna Maremanda, Hae Lin Jang, Shiladitya Sengupta. Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6158.