Antioxidant PRDX1 limits CD8+ T cell effector function in the tumour microenvironment

Abstract

CD8+ T cells have been recognised for their critical role in detecting and orchestrating effective anti-tumour immunity. However, under this selection pressure, cancer cells progressively evolve mechanisms to undermine and subvert host immunity. Immunotherapy aimed at restoring or enhancing endogenous CD8+ T cell function has had profound clinical success and exemplifies the anti-tumour potential of T cell immunity. Nevertheless, therapeutic efficacy is confined to a subset of patients and responsive cancer types, highlighting additional and poorly defined mechanisms of tumour-mediated immunosuppression. The tumour microenvironment (TME) is curated and manipulated by an evolving cancer and represents a significant barrier to effective anti-tumour immunity. While considerable attention has been placed on the cellular composition of the TME, the influence of the cell-autonomous fluid phase of the environment, termed tumour interstitial fluid (TIF), remains poorly defined. The presented research demonstrates that TIF has a highly suppressive effect on acute CD8+ T cell activation and, surprisingly, has profound antioxidant activity. Peroxiredoxin 1 (PRDX1) was identified as the most differentially enriched antioxidant protein in TIF. Individual environmental supplementation of PRDX1 was sufficient to exert both an antioxidant and suppressive effect on CD8+ T cell effector programmes, suggesting an immunosuppressive role of this antioxidant in the tumour interstitium. The genetic ablation of PRDX1 in murine models of melanoma improved immunotherapy outcomes. Furthermore, armouring CD8+ T cells with resistance to the suppressive effects of PRDX1, achieved through the overexpression of NADPH oxidase NOX2, significantly enhanced their antitumor activity in an adoptive transfer model in vivo. This research ultimately identifies PRDX1 as a novel immunosuppressive protein in the TME and the existence of a previously unrecognised redox immune checkpoint in cancer.