The miRNA Profile of Inflammatory Colorectal Tumors Identify TGF-β as a Companion Target for Checkpoint Blockade Immunotherapy

Bjarne Bartlett,Vedbar S Khadka,Muller Fabbri,Zitong Gao,Youping Deng,Monique Schukking,Peiwen Fei,Mark Menor

doi:10.3389/fcell.2021.754507

Abstract

Extrinsic factors such as expression of PD-L1 (programmed dealth-ligand 1) in the tumor microenvironment (TME) have been shown to correlate with responses to checkpoint blockade therapy. More recently two intrinsic factors related to tumor genetics, microsatellite instability (MSI), and tumor mutation burden (TMB), have been linked to high response rates to checkpoint blockade drugs. These response rates led to the first tissue-agnostic approval of any cancer therapy by the FDA for the treatment of metastatic, MSI-H tumors with anti-PD-1 immunotherapy. But there are still very few studies focusing on the association of miRNAs with immune therapy through checkpoint inhibitors. Our team sought to explore the biology of such tumors further and suggest potential companion therapeutics to current checkpoint inhibitors. Analysis by Pearson Correlation revealed 41 total miRNAs correlated with mutation burden, 62 miRNAs correlated with MSI, and 17 miRNAs correlated with PD-L1 expression. Three miRNAs were correlated with all three of these tumor features as well as M1 macrophage polarization. No miRNAs in any group were associated with overall survival. TGF-β was predicted to be influenced by these three miRNAs (p = 0.008). Exploring miRNA targets as companions to treatment by immune checkpoint blockade revealed three potential miRNA targets predicted to impact TGF-β. M1 macrophage polarization state was also associated with tumors predicted to respond to therapy by immune checkpoint blockade.

Highlights

Despite therapeutic advances and declining mortality since 1990, an estimated 50,630 patients in the United States die annually from colorectal adenocarcinomas (Siegel et al, 2018)
colon adenocarcinoma (COAD) data from The Cancer Genome Atlas was selected for analysis because many different types of analysis were available for the same patient cohort including: somatic mutation burden, microsatellite instability (MSI) status, mRNA analysis, and miRNA analysis
MSI was assessed with the MicrOSAtellite Instability Classifier (MOSAIC) from Hause et al (2016) to predict MSI status based on Whole Exome Sequencing (WES) data

Summary

Introduction

Despite therapeutic advances and declining mortality since 1990, an estimated 50,630 patients in the United States die annually from colorectal adenocarcinomas (Siegel et al, 2018). MiRNA Targets ICI Therapy ligands and receptors, are one such innovation that have shown durable anti-tumor response. A combination of both intrinsic and extrinsic tumor features has been shown to correlate with response to checkpoint blockade therapy. Extrinsic factors, such as programmed cell-death ligand 1 (PD-L1) expression in the tumor microenvironment have been shown to correlate with responses to checkpoint blockade therapy (Topalian et al, 2012). Two intrinsic factors related to tumor genetics, microsatellite instability (MSI), and tumor somatic mutation burden (TMB), have been linked to high ICI response rates (Snyder et al, 2014; Le et al, 2015). Individual tumors continue to display a range of responses to checkpoint inhibition, highlighting the need for additional research to improve biomarkers and therapeutic approaches

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