Comprehensive immune transcriptomic subtypes of colorectal cancer for development of precision immunotherapy.

Abstract

e15078 Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value<0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.