T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation

Abstract

Even in patients whose tumours exhibit increased T cell infiltration, resistance to immune checkpoint inhibitor (ICI) therapy is common. We investigated mechanisms of ICI resistance using engineered mouse models with increased neoantigen burden and T cell infiltration. We found that in ICI-resistant tumours, T cells upregulate an NF-kB-driven inflammatory circuit in the tumour microenvironment (TME), culminating in PMN-MDSC recruitment and tumour escape. This resistance circuit was molecularly driven by IL-1, TNFa, and G-CSF, and their genetic or pharmacologic inhibition increased ICI efficacy. Furthermore, we identified a subset of human TNF-expressing T cells that expand following ICI therapy and are associated with increased tumour NF-kB signaling. These data reveal a surprising mechanism of ICI resistance whereby T cells instruct NF-kB-mediated inflammation to paradoxically drive a resistance circuit in participating tumours, refining our understanding of ICI response and resistance with important therapeutic implications.