Reprogramming the tumor microenvironment with next-generation chaperone-based immunolytic agent for cancer immunotherapy

Abstract

Abstract The tumor microenvironment (TME) represents a major barrier for successful cancer immunotherapy due to tumor-associated immunosuppressive pathways that facilitate immune evasion and therapeutic resistance. We recently created a multifunctional chimeric chaperone (i.e., Flagrp170) by incorporating the flagellin-derived NF-κB-stimulating sequence for superior antigen cross-presentation and co-stimulation. Upon intralesional administration, this immunolytic agent results in profound inhibition of multiple mouse tumors including melanoma, prostate cancer, colorectal cancer, and mammary tumor. Strikingly, reprogramming the TME with Flagrp170 induces elevation of multiple Th1 cytokines such as GM-CSF, IL-12 and IFN-γ. Mechanistic studies reveal that GM-CSF is mainly produced by CD8+ T cells and is indispensable for the antitumor efficacy of in situ Flagrp170 therapy. Neutralizing GM-CSF abrogates the antitumor activity of the Flagrp170, which is associated with reduced mobilization and recruitment of dendritic cells (DCs) as well as IFN-γ-expressing T cells, suggesting that GM-CSF-derived from tumor-infiltrating T cells is essential for expansion and/or function of DCs within the TME. Our findings elucidate an immunological mechanism of action of the Flagrp170 in skewing the TME towards a Th1-polarized immunostimulatory phenotype and provide a novel approach to reprogramming the immune landscape of the TME for improved immunotherapeutic outcomes.