Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer

Abstract

Background Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. Patients and methods Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort ( N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString ® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab ( N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. Results In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (AP high ), and this was used to define the AP high tertile of the second cohort (13 AP high of 37). AP high tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the AP high group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099–0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. Conclusion A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT#02589496

Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

“…In the era of immuno-oncology, GC has revealed to be a tumor with weak immunogenicity, and despite encouraging results, the response rates in clinical trials with immune checkpoint inhibitors remain limited [ 32 , 156 ]. In this setting, emerging data on immunotherapy for GC highlight that expression of immune biomarkers is epigenetically regulated, and that epigenetic mechanisms are able to predict clinical response to immune checkpoint inhibitors [ 157 , 158 , 159 , 160 ]. Moreover, the aberrant epigenome of GC was revealed to contribute to cancer immunoediting and to immune escape of cancer cells [ 161 ].…”

Dissection of gastric cancer heterogeneity for precision oncology

“…42,57,58 Another interesting nominated biomarker is alternative promoter usage. In this respect, Sundar et al 59 showed the preliminary utility of alternative promoters in predicting benefit from PD-1 blockade in metastatic GC, where high alternative promoter burden (AP score) could potentially serve as a negative predictive biomarker.…”

Cancer Epigenomics and Beyond: Advancing the Precision Oncology Paradigm

“…Recent work surveying the epigenetic landscape of certain tumors uncovered an intriguing mechanism across a wide range of gene promoters. Qamra et al [119] and Sundar et al [120] demonstrated that tumors expressed genes from different start sites relative to paired normal tissues, thereby producing RNA transcripts differing in length and base sequence. Alternative promoter usage is known to occur in about 50% of expressed genes in normal tissues.…”