Distinct Mechanisms of Mismatch-Repair Defi ciency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma

Mismatch repair-deficient (MMRd) cancers have varied responses to immunecheckpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared with epigenetic MMRd; however, within each category of MMRd, mutation burden was not correlated with ICB response. Pretreatment JAK1 mutations were not associated with primary resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of antitumor immunity for mutational versus epigenetic MMRd cancers. Whereas effector CD8 + T cells correlated with regression of mutational MMRd tumors, activated CD16 + NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and tumor-extrinsic factors that influence ICB response. SIGNIFICANCE: The molecular mechanism of MMRd is associated with response to anti-PD-1 immunotherapy in endometrial carcinoma. Tumors with epigenetic MMRd or mutational MMRd are correlated with NK cell or CD8 + T cell-driven immunity, respectively. Classifying tumors by the mechanism of MMRd may inform clinical decision-making regarding cancer immunotherapy.

Automated summary

This study found that patients with mutational MMRd endometrial cancer had higher response rates and longer survival after treatment with the PD-1 inhibitor pembrolizumab compared to those with epigenetic MMRd. However, mutation burden did not correlate with immune checkpoint blockade response. The study also revealed different modes of antitumor immunity between mutational and epigenetic MMRd cancers.