Alteration in the Immune Microenvironment Based on APC Status in MSS/pMMR Colon Cancer

Abstract

Introduction. Immunotherapy is currently the most promising antitumor treatment approach. However, the colon cancer immunotherapy indication dMMR/MSI-H do not cover all colon cancer patients suitable for immunotherapy. We performed transcriptome-wide expression profile analyses of pMMR/MSS colon adenocarcinoma (COAD) specimens from TCGA database to identify a genetype signature associated with tumor immune microenvironment types (TIMTs). Methods. TCGA database was used to identify tumor genotypes suitable for antitumor immunotherapy. We analyzed RNA-sequencing profiles of 338 COAD targeted to the pMMR/MSS group from TCGA public dataset. The ESTIMATE and the CIBERSORT were used to analyze the pMMR/MSS COAD immune microenvironment between APC wild and APC mutation. Furthermore, we further verified the relationship between APC genotype and TIMTs and the efficacy of immunotherapy in 42 colon cancer specimens. Results. We identified that in APC-wt/MSS colon cancer, the expressions of PD-1, PD-L1, CTLA4, and CYT (GZMA and PRF1) were increased. The TMB, Immunoscore, and the proportion of CT8+ T cell infiltration also were identified increasing in these patients. And pathway enrichment analysis for differentially expressed genes (DEGs) between APC-wt and APC-mt MSS COAD was done to further explore their biological function. Similarly, the significant pathways for DEGs were mainly enriched in the immune response, extracellular matrix, and cell adhesion which involved in immune response. Specimens from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Moreover, APC-wt was compared with APC-mt MSS/pMMR colon cancer (DOR, 45% and 26.7%, respectively; $P<0.05$ ). Conclusion. Based on the results, we found that more colon cancers of APC-wt/MSS are classified by TMIT I. And APC-wt/MSS colon cancer patients are more likely to benefit from antitumor immunotherapy.