Editors' ChoiceCancer Immunology

Inflammation helps tumors evade immune detection

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Science Signaling  20 Dec 2016:
Vol. 9, Issue 459, pp. ec300
DOI: 10.1126/scisignal.aam6078

Inflammation in the tumor microenvironment stimulates the recruitment of innate immune cells, but chronic inflammation suppresses cytotoxic T cell activity and is associated with tumor progression. Lim et al. found that inflammation increased the abundance of immune checkpoint ligand PD-L1 on the surface of tumor cells through a posttranslational mechanism. Various cell-based, biochemical, and proteomic assays using human cancer cell lines of various types, T cell cocultures, and an immunocompetent mouse model of basal-like breast cancer revealed that macrophage-derived proinflammatory tumor necrosis factor–α (TNF-α) stimulated nuclear factor κB (NF-κB) signaling in tumor cells. The activated NF-κB subunit p65 bound the promoter of the gene encoding COP9 signalosome 5 (CSN5). CSN5 abundance correlated with less K48-linked ubiquitylation and greater stabilization of PD-L1. Knocking down CSN5 before implantation or treating tumor-bearing mice with curcumin, a compound found in edible plants that inhibits NF-κB signaling, reduced PD-L1 abundance, inhibited tumor growth, and increased the potency of CTLA4 antibody therapy without detectable systemic toxicity. NF-κB activation is already well associated with tumor cell survival in various contexts, but single therapies that inhibit NF-κB signaling have failed clinically because of adverse side effects in patients (see coverage by Grinberg-Bleyer and Ghosh). However, the findings from Lim et al. emphasize the importance of NF-κB signaling to tumor cell survival, now through an immune evasion mechanism. This mechanism suggests that a combination therapy of a natural inhibitor of NF-κB signaling, such as curcumin, at a dose high enough to reduce CSN5 abundance but not sufficient to independently kill the tumor with an immunotherapy drug may be clinically effective with fewer side effects than therapies that attempt to kill the tumor by inhibiting NF-κB signaling.

S.-O. Lim, C.-W. Li, W. Xia, J.-H. Cha, L.-C. Chan, Y. Wu, S.-S. Chang, W.-C. Lin, J.-M. Hsu, Y.-H. Hsu, T. Kim, W.-C. Chang, J. L. Hsu, H. Yamaguchi, Q. Ding, Y. Wang, Y. Yang, C.-H. Chen, A. A. Sahin, D. Yu, G. N. Hortobagyi, M.-C. Hung, Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell 30, 925–939 (2016). [PubMed]

Y. Grinberg-Bleyer, S. Ghosh, A novel link between inflammation and cancer. Cancer Cell 30, 829–830 (2016). [PubMed]

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