Abstract

Abstract The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses 1,2 . Within the tumour microenvironment, CD8 + T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches 3–7 . Although interactions with type 1 conventional dendritic cells have been implicated in this process 3–5,8–10 , the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9 , Cxcl10 and Il15 , but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E 2 (PGE 2 ), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE 2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE 2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.