Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer
Elevated tumor-infiltrating lymphocytes (TILs) 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, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity.
Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition.
High CYT 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. CYT-high CRC patients had improved overall survival (p = 0.019) and disease-free survival (p = 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- 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 (ICMs)—programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)—correlated significantly with CYT (p < 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients.
High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.
Kazuaki Takabe is supported by National Institutes of Health/National Cancer Institute (NIH/NCI) Grant R01CA160688 and Susan G. Komen Investigator Initiated Research grant IIR12222224, and is also supported by Institutional Startup Grant 71-4085-01. This work was also supported by NCI Grant P30CA016056 involving the use of Roswell Park Cancer Institute’s Bioinformatics and Biostatistics Shared Resources.
SN, TK, LY, and KT had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: SN, TK, and KT. Acquisition, analysis, or interpretation of data: SN, TK, LY, QQ, and XP. Drafting of the manuscript: SN, TK, LY, QQ, XP, and KT. Critical revision of the manuscript for important intellectual content: SN, TK, and KT. Statistical analysis: TK, LY, QQ, and XP. Obtained funding: KT. Administrative, technical, or material support: LY, QQ, XP. Study supervision: TK and KT.
Sumana Narayanan, Tsutomu Kawaguchi, Li Yan, Xuan Peng, Qianya Qi, and Kazuaki Takabe have no potential conflicts of interest to declare.
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