A delicate interplay between adaptive and innate immunity caused by immunotherapy triggers tumor immunity and aseptic inflammation

Abstract

Abstract Successful immune-based therapies that treat tumors are often accompanied by immune-related adverse events (irAE). Immunotherapy-treated patients who experience favorable anti-tumor responses typically manifest irAEs. The primary immunotherapies currently in clinic include agents that activate T cell responses such as checkpoint blockade of inhibitory pathways and infusion of ex-vivo tumor-derived or T cell receptor (TCR)-transgenic or chimeric antigen receptor (CAR)-modified T cells. While the beneficial and toxic effects of T cell-based immunotherapies in the clinic are being extensively explored, the precise mechanisms of tumor elimination and irAE remain the subject of intense investigation. In the present study, we treated established tumors with melanoma-specific adoptive CD4+ T cell transfer and costimulation via anti-OX40 or anti-CTLA-4. We found that, in spite of co-opting the adaptive immune response, acute local inflammation plays a fundamental role in tumor elimination and related toxicities in a model irAE. While stimulated T cells are necessary for initiating a therapeutic response, activation of endogenous neutrophils constitute an important and necessary effector mechanism of tumor destruction and irAE. Extensive neutrophils extracellular traps (NETs) were associated with irAE. Melanoma patients treated with checkpoint blockade, suffering from skin rashes equivalent to irEA found in mice, showed increased survival and NETois in biopsies from rashes and tumors. Our results bring forward a novel paradigm where T cells prime an anti-tumor immune response followed by an inflammatory effector mechanism, provided by the innate immune system with curative as well as morbid effects.