Immune effector dysfunction signatures predict outcomes in patients with colorectal cancer

•High NK and CD8+ T cells were associated with poor prognosis in CRC patients.•Abnormal alteration of IED genes CCR9, ISG20, ICOS and CACNA2D2 predicted outcomes.•High-risk score estimated by IED genes predicted poor prognosis.•Risk stratification was constructed by combining risk score and TNM stage. Immune effector dysfunction (IED) is mainly manifested as immune exhaustion and senescence, which are the primary obstacles to the success of cancer immunotherapy. In the current study, we characterized the prognostic relevance of IED signatures in patients with colorectal cancer (CRC). Immunohistochemistry (IHC) data of CRC tissue samples from 41 newly diagnosed patients in our clinical center (HDPH cohort) were used to investigate the prognostic importance of IED signatures. The results were validated by the RNA sequencing data of 372 CRC patients from the Cancer Genome Atlas (TCGA) database. In the HDPH cohorts, high Natural Killer (NK) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with poor overall survival (OS) and relapse-free survival (RFS) in CRC patients. Optimal IED signatures, including high expression of CCR9, ISG20, and low expression of ICOS, and CACNA2D2, predicted poor OS and RFS. Moreover, high-risk scores estimated by a weighted combination of these four IED genes were associated with poor OS and RFS. Notably, risk stratification was constructed by combining risk score and tumor node metastasis (TNM) stage better than TNM stage alone in predicting OS and RFS for CRC patients. The above results were confirmed in the TCGA cohort. CCR9, ISG20, ICOS, and CACNA2D2 were optimal IED signatures for predicting the outcomes of CRC patients, which might be a potential biomarker for prognostic stratification and designing novel CRC therapy.