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MicroRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Anti-tumor Immune Response and Poor Outcomes of Patients

ABSTRACT: BACKGROUND & AIMS: Immune checkpoint inhibition may affect outcomes of highly aggressive cancers, such as esophageal adenocarcinoma (EAC). In this regard, the MHC-I pathway and the tumor immune microenvironment are key factors that need to be explored. METHODS: We investigated post-transcriptional mechanisms of MHC-I regulation through functional and molecular studies of EAC cell lines and of EAC biopsies. We performed RNA-sequencing of fifty-one treatment-naïve EAC biopsies to evaluate the status of the MHC-I pathway and the tumor immune microenvironment with respect to patient response and disease outcomes. RESULTS: We found that in EAC miR-125a-5p and miR-148a-3p regulate TAP2 and MHC-I expression. Interestingly, MHC-I pathway expression correlated with poorer therapeutic response. Moreover, MHC-I status correlated with a tumor immune-inflamed microenvironment, in which upregulation of PD-L1, PD-L2 and IDO1 were associated to worse patient survival. CONCLUSIONS: Our data indicate that EAC patients with a proficient MHC-I expression and a tumor immune-inflamed microenvironment have poorer outcomes after neo-adjuvant therapy and may benefit from immune checkpoint inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112926 | GEO | 2020/12/31

REPOSITORIES: GEO

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Project description:Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (B2M), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified B2M aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping B2M, and absence of tumor-specific B2M protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that B2M LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of B2M was found only in nonresponders. We also found evidence for association of LOH overlapping IFNGR1 with poorer overall survival exclusively in the anti-PD1 cohort. Thus, B2M loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.

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MicroRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Anti-tumor Immune Response and Poor Outcomes of Patients

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