Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.

Overview

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 E₂ (PGE₂), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE₂ 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 PGE₂ and IFN-I, and proposes rational combination therapies to enhance immunotherapies.