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

Immunity
Eduardo BonavitaSantiago Zelenay

Abstract

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.

Citations

Feb 11, 2021·Immunological Reviews·Nicoletta CaronniRenato Ostuni
Mar 23, 2021·Nature Reviews. Cancer·Suchit JhunjhunwalaLélia Delamarre
Apr 30, 2021·Nature Reviews. Immunology·Mark Schmitt, Florian R Greten
Jun 20, 2021·European Journal of Immunology·Olivier DemariaEric Vivier
Jul 16, 2021·Journal for Immunotherapy of Cancer·Hiroshi ImazekiChie Kudo-Saito
Aug 17, 2021·Frontiers in Immunology·Mercedes Beatriz FuertesNorberto Walter Zwirner
Aug 27, 2021·Translational Oncology·Lizhi PangSteven Qian
Aug 26, 2021·Patterns·Óscar Lapuente-SantanaFederica Eduati

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Datasets Mentioned

BETA
GSE139047
GSE139044
GSE139045
GSE139046
GM-1
EGAS00001002928
PRJEB25780
PRJEB23709
GSE78220
GSE91061

Methods Mentioned

BETA
flow cytometry
fluorescence-activated cell sorting
FACS
ELISA
PCR
Chip
Illumina sequencing

Software Mentioned

IMVigor210Biologies R package
MATLAB
cBioPortal
MCPcounter
featureCounts
Cytobank
BBMAP
FlowJo
R
Ingenuity Pathways Analysis software ( IPA )

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