Editors' ChoiceCancer Immunotherapy

Refining precision immunotherapy

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Science Signaling  19 Jan 2021:
Vol. 14, Issue 666, eabg5661
DOI: 10.1126/scisignal.abg5661

Two studies show why some, but not all, MMR-deficient tumors are sensitive to immunotherapy.

A high mutation load in tumors typically predicts the efficacy of immunotherapy. However, two studies show that this trait alone is insufficient to confer sensitivity to immunotherapy. Specifically, some mismatch repair (MMR)–deficient cancers are insensitive to immunotherapy. Lu et al. and Guan et al. found that loss of the mismatch repair protein MLH1 activated the cGAS-STING cytosolic DNA–sensing pathway and subsequent secretion of interferon-β that primed T cells. More specifically, loss of an exonuclease-regulating subunit of MLH1 (which is seen in about half of MMR-deficient tumors) enabled an aberrantly high amount of DNA excision, sending nuclear DNA into the cytoplasm and triggering cGAS-STING signaling. Deficient expression of components of the cGAS-STING pathway correlated with decreased T cell infiltration into tumors, resulting in resistance to checkpoint blockade therapy. These studies refine our understanding of the mechanisms underlying immunotherapy sensitivity in MMR-deficient tumors and identify biomarkers for predicting efficacy in patients (see commentary by Gerlinger).

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