Editors' ChoiceCancer

Poster child: Ready for a close-up

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Science Translational Medicine  06 Apr 2016:
Vol. 8, Issue 333, pp. 333ec54
DOI: 10.1126/scitranslmed.aaf6931

Checkpoint inhibitors are antibodies that block inhibitory signals, thereby activating the immune system. As the disease where checkpoint inhibitors first proved their mettle, melanoma is the “poster child” for checkpoint blockade. Yet, the majority (60 to 70%) of patients do not respond to treatment. A deeper understanding of the factors that correlate with response could help to prospectively identify patients likely to benefit from treatment, and could also shed light on future rational combinations of agents in order to increase response rates.

Hugo et al. sequenced whole exomes of samples from patients before treatment with the programmed cell death 1 (PD1) antagonists nivolumab or pembrolizumab and found that mutational load significantly correlated with survival. RNA sequencing showed that “mesenchymal and inflammatory” tumor phenotypes correlated with resistance to PD1 blockade. Specifically, this meant that mesenchymal transition genes, immunosuppressive genes (such as IL10), and monocyte/macrophage chemotactic genes were enriched in nonresponding patients. Interestingly, genes related to T cells—a major target of PD1 activity—were not differentially expressed in responders compared with nonresponders. This overall pattern could be further broken down into 26 transcriptomic signatures that were co-enriched in most nonresponding tumors. The authors termed this the “innate anti-PD1 resistance signature” (IPRES). IPRES was not differentially expressed in a control cohort of patients treated with inhibitors of CTLA4—another immune checkpoint protein—suggesting divergent mechanisms of resistance for different types of checkpoint blockade.

Future studies will need to decipher whether and which components of the IPRES are causal and which are merely associated with checkpoint inhibitor failure. A robust association may help to prospectively assign patients to the treatment best suited for them, but a mechanistic understanding will ultimately point toward future rational combinations of checkpoint inhibitors with other immunotherapeutic agents to enhance response and survival.

W. Hugo et al., Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016). [Abstract]

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