T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

Abstract

A key phenomenon in cancer is the establishment of a highly immunosuppressive tumor microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumor recognition and hence hereof tumor eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumor is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signaling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and type I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggest a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFN gamma carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumor by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME

“…The irradiated tumor-derived exosomes also increase antitumor CD8 + T cell responses in vivo [ 198 ]. Additionally, EVs derived from activated CD4 + T cells (T-EVs) carrying IFN-γ sensitize TAMs via STING activation (without cGAS and cGAMP involvement) to repolarize them to antitumor M1 macrophages in TIME [ 199 ]. Hence, T-EVs are another option to repolarize immunosuppressive TAMs to antitumor M1 macrophages to enhance the antitumoral function of cGAMP.…”