Cytolytic Activity Score to assess Anticancer Immunity in Colorectal Cancer

Abstract

Background:

Elevated tumor infiltrating lymphocytes (TIL) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as Perforin (PRF1) and pro-apoptotic Granzymes (GZMA) to attack cancer cells, Cytolytic Activity Score (CAS) would be a useful tool to assess anticancer immunity.

Methods:

Genomic expression data was obtained from 456 patients from The Cancer Genome Atlas (TCGA). CAS was defined by GZMA and PRF1 expression. CIBERSORT was used to evaluate intra-tumoral immune cell composition.

Results:

High CAS was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+ T cells, gamma delta T cells and M1 macrophages. CAS-high CRC patients had improved OS ( p=0.019) and DFS ( p=0.016) compared to CAS-low, especially in TIL-positive tumors. Multivariate analysis demonstrated that CAS-high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability and TIL positivity. The levels of immune checkpoint molecules (ICM)- PD-1, PD-L1, CTLA4, LAG-3, TIM3 and IDO1 correlated significantly with CAS ( p<0.0001); with improved survival in CAS-high, ICM-low patients and poorer survival in ICM-high patients.

Conclusions:

High CAS within CRC associated with improved survival likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CAS also associated with high expression of immune checkpoint molecules, thus further studies to elucidate the role of CAS as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.