Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

By S. Zelenay, Annemarthe G. van der Veen, Jan P. Böttcher, Kathryn J. Snelgrove, N. Rogers, S. Acton, P. Chakravarty, M. R. Girotti, R. Marais, Sergio A. Quezada and 2 more. Cell, 2015

1,014 citations recorded by the source corpus.

Summary The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant BrafV600E mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in BrafV600E mouse melanoma cells, as well as in NrasG12D melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways. This mouse COX-dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing for COX activity as a driver of immune suppression across species. Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients.

Subfields: Oncology, Pharmacology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/f579b34d60d29ec2dca400dd50a3cc37985e56bf

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In Psychiatry and Mental health

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Citations in the corpus

• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, background): “It is well known that PGE2 negatively affects anti-tumor immune responses and inhibition of cyclooxygenases (COX) 2 can sensitize ICB in tumor bearing animal models (Bottcher et al., 2018; Li et al., 2016; Zelenay et al., 2015).”
• NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control (2018, methodology): “Similar to Ptgs1/Ptgs2 / BRAFV600E tumors, B16-OVA tumors (that do not produce PGE2) (Zelenay et al., 2015) expressing CCL5 and XCL1 showed increased accumulation of cDC1 within the TME (Figure 5G) and decreased tumor growth (Figure 5H).”
• Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “…microbiota products that stimulate biological activities within the host, e.g., butyrate), or carefully selected antibiotics (i.e., that target an undesirable bacterial population) alongside ICBs could yield alternative combinatorial regimens of promise to cancer patients (Zitvogel et al., 2015).”