Abstract 4058: The miRNA expression profile of inflammatory tumors reveals a unique immune cell profile and potential companion targets for checkpoint blockade immunotherapy
Authors: Bjarne Bartlett, Vedbar Khadka, Mark Menor, Youping Deng
Journal: Cancer Research (2019)

Abstract Background: Extrinsic factors such as expression of PD-L1 (programmed death-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. Our team sought to explore the biology of such tumors further and suggest potential companion therapeutics to current checkpoint inhibitors. Methods: A CRC patient cohort (n=549) from TCGA was used for analysis. MSI was assessed with the MicrOSAtellite Instability Classifier (MOSAIC). TMB was assessed using Mutect2 and a 5% cutoff for allele frequency. Tumors with &amp;gt;20 somatic mutations per megabase were classified as high mutation. Expression of PD-L1 was assessed by quantifying gene expression – FPKM values from TCGA were used for this. Immune cell populations were analyzed using 3 algorithms: CIBERSORT, TIMER, and xCell. Pathway analysis was conducted with miRbase, an online tool for analyzing gene targets for miRNAs. Results: Analysis by Pearson Correlation revealed 41 miRNAs correlated with mutation burden, 62 miRNAs correlated with microsatellite instability, and 17 miRNAs correlated with PD-L1 expression. Fifteen of these miRNAs were correlated with all 3 tumor features and chosen for further analysis. let-7i, mir-1266, mir-132, mir-146b, mir-155, mir-212, mir-22, mir-223, mir-511, mir-625, and mir-629 were associated positively associated with the 3 tumor features while mir-335, mir-552, and mir-92a-2 were negatively associated with all 3. None of these miRNAs were associated with overall survival. Two cellular pathways known to influence immunological function were predicted by miRbase to be targeted by the miRNAs: PI3K-Akt (p&amp;lt;1e-16) and TGF-beta (p=1.52e-14). Three immune cell deconvolution algorithms were employed to further explore the link between PI3K-Akt/TGF-beta and the TME. A significant link was found between the M1 macrophage polarization and tumors displaying the 3 features indicating favorable responses to immunotherapy. All 3 features were associated the proportion of M1 macrophages: PD-L1 expression (p&amp;lt;2.2e-16), MSI status (P=.001), and TMB (P=1.5e-06). Similar results were found with both TIMER and xCell. Conclusions: Exploring miRNA targets as companions to treatment by immune checkpoint blockade revealed 15 potential miRNA targets predicted to impact 2 important cellular pathways: PI3K-Akt and TGF-beta. M1 polarization of macrophages was also associated with tumors predicted to respond to therapy by immune checkpoint blockade. Citation Format: Bjarne Bartlett, Vedbar Khadka, Mark Menor, Youping Deng. The miRNA expression profile of inflammatory tumors reveals a unique immune cell profile and potential companion targets for checkpoint blockade immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4058.