Modulating tumoral exosomes and fibroblast phenotype using nanoliposomes augments cancer immunotherapy

Abstract

Cancer cells program fibroblasts into cancer associated fibroblasts (CAFs) in a two-step manner. First, cancer cells secrete exosomes to program quiescent fibroblasts into activated CAFs. Second, cancer cells maintain the CAF phenotype via activation of signal transduction pathways. We rationalized that inhibiting this two-step process can normalize CAFs into quiescent fibroblasts and augment the efficacy of immunotherapy. We show that cancer cell–targeted nanoliposomes that inhibit sequential steps of exosome biogenesis and release from lung cancer cells block the differentiation of lung fibroblasts into CAFs. In parallel, we demonstrate that CAF-targeted nanoliposomes that block two distinct nodes in fibroblast growth factor receptor (FGFR)–Wnt/β-catenin signaling pathway can reverse activate CAFs into quiescent fibroblasts. Co-administration of both nanoliposomes significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 in immunocompetent lung cancer–bearing mice. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling constitutes a promising approach to augment immunotherapy.

CD8+ T cell-based cancer immunotherapy

“…In a murine lung cancer model, nanosized liposomes were loaded with dual inhibitors against both exosome biogenesis and release and coupled with antibodies against epithelial cell adhesion molecule, targeting and shifting cancer associated fibroblasts into quiescent fibroblasts. This TME reversal increased the cytotoxic T cell infiltration and augmented antitumor efficacy of PD-L1 antibody when administered synergistically [ 150 ]. Moreover, magnetic iron oxide nanoparticles with cationic polymer functionalization were internalized by myeloid-derived suppressor cells (MDSCs) (mainly TAMs) in brain tumor.…”