Abstract 69: Versican proteolysis signature as a potential immune infiltration biomarker for colorectal cancer

Abstract

Abstract Background: A subset of patients with mismatch repair proficient colorectal cancers (CRCs) benefit from immunotherapies, though currently no markers predict which cancers are likely to respond. Our group demonstrated that versican (VCAN), an immunoregulatory tumor matrix proteoglycan, when proteolyzed to an immunostimulatory fragment called versikine (Vkine) results in enhanced CD8+ T cell infiltration across multiple cancers. Here we evaluate if a RNA expression signature of VCAN proteolysis can identify CRCs with an immune cell infiltrated phenotype. Methods: The TCGA PanCancer Atlas colorectal adenocarcinoma dataset (594 patients (pts)) was divided into cohorts based on RNA expression Z-scores for VCAN, TIMP3, and ADAMTS4. The VCAN proteolytic predominant (VPP) cohort (Z-score VCAN >0, TIMP3 <0.5, ADAMST4 >0) was compared to the VCAN proteolytic weak (VPW) cohort (Z-score VCAN >0, TIMP3 >0.5, ADAMST4 >0). Differences in clinical characteristics, mutation profile, differential gene expression, and gene set enrichment analysis (GSEA) were evaluated. Results: The VPP group consisted of 42 pts (20:22 female: male, median age: 68.5 years old). The VPW group consisted of 29 pts (12:17 female: male, median age: 64 years old). The two groups had no significant difference between stages of disease. There was a significant increase in the mutation count in the VPP cohort (VPP median=115.5, VPW median=91, p=0.045). The MSI MANTIS scores were not different between the cohorts (VPP median=0.35, VPW median=0.37, p=0.325). The VPP cohort was enriched for gene sets associated with immune cell infiltration (interferon gamma response (FDR q<0.001), inflammatory response (FDR q<0.001), complement (FDR q<0.001), TNFA signaling via NKFB (FDR q<0.001), IL2 STAT5 signaling (FDR q<0.001), and IL6 JAK STAT3 signaling (FDR q<0.001). The VPW cohort was enriched for gene sets involving cell proliferation (WNT beta catenin signaling (FDR q<0.214), hedgehog signaling (FDR q<0.190), and KRAS signaling DN (q<0.159). Specifically, the VPP group demonstrated enhanced expression of CD274 (PD-L1; log2FC=1.41, p<0.001), LAG3(log2FC=1.41, p<0.001), PDF1(log2FC=1.34, p<0.001), CD8A(log2FC=1.25, p<0.001), CXCL9(log2FC=1.19, p=0.001), CXCL10(log2FC=1.44, p=0.001), IL6(log2FC=2.23, p<0.001), and CD19(log2FC=1.26, p<0.001). Conclusion: VPP expression signature correlates with immune infiltration based on RNA expression and deserves further investigation to predict response to immunotherapies in CRC as well as other cancer types. Citation Format: Derek Buckalew, Sean Kraus, Katie Johnson, Cheri A. Pasch, Dustin A. Deming. Versican proteolysis signature as a potential immune infiltration biomarker for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 69.