Correlation of exploration of immune profile and genomic with microsatellite stable/tumor mutational burden-low colorectal cancer.

Abstract

213 Background: Microsatellite stable/tumor mutational burden-low (MSS/TMB-L) tumors, represent the majority of colorectal cancer (CRC) patients and derive limited benefit from immune checkpoint inhibitors (ICI). Given the vast heterogeneity of this population, some patients may be candidates for ICI. Herein, we study the tumor immune microenvironment (TIME) and genomic correlates associated with favorable immune response in MSS/ TMB-L CRC patients. Methods: Using The Cancer Genomic Atlas Colorectal Adenocarcinoma (TCGA-COAD) cohort (n = 594), MSS patients (MSI Mantis score < 0.4) with TMB-L (<10 mutations/megabase) were identified. The CIBERSORT algorithm was used to calculate the fraction of 22 immune cells using RNA-seq data. Relevant immune expression signatures from the CRI iAtlas were used to assess TIME profiles. An antitumor immune activity (AIA) score was constructed using CD8+ T cells, T regulatory cells, and M1 & M2 macrophage fractions. Enriched mutations in MSS/ TMB-L patients with favorable antitumor immune scores were identified and used to stratify patients into favorable and unfavorable immune profiles (FIP & UIP). Comparisons were made using the Mann-Whitney U T-test and Fisher’s exact test. Results: We identified 430 (72.4%) MSS/TMB-L patients among the TCGA-COAD cohort. The AIA score ranged from – 0.44 to 0.62 (higher scores denote favorable AIA activity). The majority of patients (77%) had scores < 0. Top enriched mutated genes associated with higher scores included HMX2, BBS12, IFNLR1, SLC30A2, WDR48, ZNF329, H4C11, PARD3B, ENAM, ASCC1, CCDC88B, CMKLR1, IL21, KLHL11, and OTOP2. Patients harboring a mutation in one or more of these 15 genes were categorized in the FIP group (n=50, 11.6%) and patients with no mutations were categorized in the UIP group (n=360, 88.4%). The FIP group had significantly (p < 0.05) higher levels of TMB, CD8+ T cells, activated NK cells, M1 macrophages, immunogenic SNV mutations, and cytotoxic activity while patients with UIP had higher levels (p < 0.05) of M2 macrophages, neutrophils, and a trend for higher regulatory T cells and TH17 cells. Gene set enrichment analysis showed upregulation of T cell proliferation, interferon signaling, and Fanconi anemia pathway in FIP. Compared to UIP, FIP patients had a trend for better disease-specific survival after adjustment for CC subtype (colon vs. rectum) and age (HR: 0.26, 95% CI: 0.06-1.09, p = 0.066). Conclusions: Findings from this analysis highlight a subset of MSS/TMB-L CRC patients, with features of favorable anti-tumor immune response and unique mutation profile, that might derive benefit from immunotherapy. Further investigation is underway to further explore the genomic correlates in this subset of patients.