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

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.
Competing Interests: Competing interests: The laboratories of A.C.O. and J.Z. received research support and funding from Boehringer Ingelheim. J.Z. is a founder and scientific advisor of Quantro Therapeutics. G.C. has received grants from Celgene, Boehringer-Ingelheim, Roche, BMS, Iovance Therapeutics, and Kite Pharma. The institution that G.C. is affiliated with has received fees for his participation on an advisory board or for presentation at a company-sponsored symposium from Genentech, Roche, BMS, AstraZeneca, NextCure, Geneos Tx, and Sanofi/Avensis. G.C. has patents in the domain of antibodies and vaccines targeting the tumour vasculature, as well as technologies related to T cell expansion and engineering for T cell therapy. G.C. has received royalties from the University of Pennsylvania regarding CAR T cell technology. G.C. is a named inventor on patent applications filed by the Ludwig Institute for Cancer Research pertaining to the subject matter disclosed herein. D.D.L. has received a grant from Hoffmann-La Roche. All other authors declare no competing interests.
(© 2024. The Author(s).)