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

Abstract

Mismatch repair-deficient (MMRd) cancers have varied responses to immune checkpoint blockade (ICB). We conducted a phase 2 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 to epigenetic MMRd; however, within each category of MMRd, mutation burden was not correlated with ICB response. Pre-treatment JAK1 mutations were not associated with primary resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of anti-tumor immunity for mutational vs. 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 extrinsic factors that influence ICB response.

Base editing screens map mutations affecting interferon-γ signaling in cancer

“… 56 , 58 We also discovered a splice mutation in JAK1 as a LOF variant (Arg110 splice variant); however, this tumor mutation was recorded in a patient with a partial response to anti-CTLA-4. 56 This highlights that the presence or absence of LOF variants in the IFN-γ pathway in a tumor biopsy is not an absolute determinant of ICB response 64 ; rather, the outcome depends on multiple factors, including the penetrance of the mutation itself (i.e., zygosity), tumor clonal architecture, co-occurring mutations, tumor mutational burden, oncogenic signaling, tumor microenvironment, antigen presentation, and immune checkpoint engagement. 4 , 65 Many of the variants we discovered with functional effects on IFN-γ signaling had clinical precedence, implying that immunoediting in cancer, particularly for immune-hot tumors, may be more prevalent than previously thought.…”

Moving into the modern era of molecular classification for endometrial cancer

“…Clinicopathologic and molecular heterogeneity within molecular subtypes has been noted (Figure 2). Our team and others have shown that the clinicopathologic features of MMR‐deficient/MSI‐H ECs differ according to the mechanism underpinning MSI instability 39–41 . MLH1 ‐hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations 39 .…”

“…37 ECs differ according to the mechanism underpinning MSI instability. [39][40][41] MLH1-hypermethylated ECs were shown to be older, more obese, and had more advanced disease at diagnosis compared to those with germline or somatic MMR gene mutations. 39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic).…”

“…39 Furthermore, there is evidence to suggest that at least a subset of MLH1 hypermethylated EC patients have worse oncologic outcomes and response to ICB when compared to their gene-mutated counterparts (germline/somatic). [39][40][41] CN-low ECs, also referred to as of NSMP, is a heterogeneous group of ECs classified by exclusion and encompassing tumors that do not display any of the other three defining molecular subtype features (i.e., POLE mutation, MSI, p53/TP53 alteration). 8,42 Several studies have focused on this NSMP group and showed that based on PTEN/PIK3CA mutation status, histology/grade, chromosome 1q gain/amplification, ER status or chromosomal instability, subgroups with distinct outcomes could be identified.…”

A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers

“…Effector CD8þ T cells correlated with regression of mutational MMR-D tumors and activated CD16þ natural killer cells were associated with response to ICI in ECs with MLH1 promoter hypermethylation. 78 This suggests heterogeneity by mechanism of MMR-D that could influence response to immune-based therapies (Table 2). However, the study was limited in sample size and did not include germline assessments.…”