Cancer cells impair monocyte-mediated T cell stimulation to evade immunity
Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, T Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Kręcioch, Jonas Bayerl, Anna‐Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta, Anna C. Obenauf
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.