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

Affiliations

• Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
• Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
• Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
• Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
• Lund University Cancer Center, Division of Oncology, Lund University, Lund, Sweden
• Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
• Department of Oncology, University Hospital of Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
• Agora Research Center, Lausanne, Switzerland
• Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
• Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
• Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
• Department of Dermatology, Medical University of Vienna, Vienna, Austria
• Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland

PMID:    DOI: 10.1038/s41586-024-08257-4

Abstract

The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches. Although interactions with type conventional dendritic cells have been implicated in this process, 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.

肿瘤微环境由癌细胞所调控，对抗肿瘤免疫反应具有重要影响。在这一微环境中，CD8+ T细胞在特定的免疫微环境中经历完全的效应分化，获得细胞毒性功能以对抗肿瘤。尽管常规1型树突状细胞在这一过程中发挥作用，但其具体的细胞参与者和分子机制仍不完全清楚。我们的研究发现，炎症性单核细胞在肿瘤内对T细胞的激活过程中起着关键作用。这些细胞能够表达CXCL9、CXCL10和IL-15，但与常规1型树突状细胞通过交叉呈递抗原不同，炎症性单核细胞通过“交叉穿戴”的方式，获取并呈递来自肿瘤细胞的肽-MHC I复合物。癌细胞中的MAPK信号通路超激活会抑制这一过程，它通过同时抑制I型干扰素（IFN-I）的产生并促使前列腺素E2（PGE2）的分泌，削弱了炎症性单核细胞的功能，并抑制了肿瘤内T细胞的激活。通过增强IFN-I的产生和阻断PGE2的分泌，可以恢复这一过程，重新激活T细胞介导的免疫反应。综上所述，我们的研究揭示了炎症性单核细胞在肿瘤内T细胞激活中的核心作用，阐明了肿瘤细胞如何通过反向调控PGE2和IFN-I信号，干扰T细胞的免疫反应，并提出了通过联合疗法增强免疫治疗效果的合理策略。