Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 6; pp. 1215 - 1229.e8
• Main Authors: Bonavita, Eduardo, Bromley, Christian P., Jonsson, Gustav, Pelly, Victoria S., Sahoo, Sudhakar, Walwyn-Brown, Katherine, Mensurado, Sofia, Moeini, Agrin, Flanagan, Eimear, Bell, Charlotte R., Chiang, Shih-Chieh, Chikkanna-Gowda, C.P., Rogers, Neil, Silva-Santos, Bruno, Jaillon, Sebastien, Mantovani, Alberto, Reis e Sousa, Caetano, Guerra, Nadia, Davis, Daniel M., Zelenay, Santiago
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2020; Elsevier; Elsevier Limited; Cell Press
• Subjects: Ablation; Adaptive immunity; Animals; Cancer; cancer-related inflammation; Cytotoxic T cells; Cytotoxicity; Depth profiling; Dinoprostone - metabolism; Gene expression; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - therapeutic use; Immune evasion; Immunotherapy; Inflammation; Inflammation - genetics; Inflammation - immunology; Interferon; interferon-gamma; Interferon-gamma - metabolism; Killer Cells, Natural - immunology; Lymphocytes; Lymphocytes T; Melanoma; Mice; Microenvironments; Natural killer cells; Neoplasms - immunology; Neoplasms - therapy; Neutrophils; NK cells; Patients; Phenotype; Phenotypes; Prognosis; Prostaglandin E2; Prostaglandin-Endoperoxide Synthases - genetics; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism; T-Lymphocytes, Cytotoxic - immunology; Tumor Escape - immunology; Tumor immunity; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; γ-Interferon; NK cells; immune evasion; prostaglandin E2; immunotherapy; cancer-related inflammation; tumor immunity; tumor microenvironment; cytotoxic T cells; interferon-gamma
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.10.020

Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes. [Display omitted] •NK cells drive broad inflammatory remodeling characteristic of T-cell-inflamed tumors•PGE2 acting on EP2 and EP4 on NK cells prevents the TME switch enabling immune escape•Opposing inflammatory profiles found in many human cancer types have prognostic value•A signature capturing pro- and anti-tumor factors predicts response to immunotherapy Inflammation can fuel or suppress cancer. Bonavita et al. identify NK cells as primary orchestrators of T cell inflammation in murine models and devise an inflammatory signature that predicts patient survival and response to immunotherapy in multiple malignancies.