CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery

In this study, we aimed to assess the prognostic value of CD226 on tumor-infiltrating lymphocytes derived from liver metastases of colorectal cancer (CRC) patients treated with chemotherapy and radical surgery. CD226high expression was associated with a potent immune infiltrate in RNAseq from primary colorectal cancer and liver metastases. CD226 expression contributes to defining the immune contexture of CRC liver metastases and primary tumors. In liver metastases, CD226 expression on CD8 T cells was not specifically co-expressed with other immune checkpoints such as PD1, TIGIT and TIM3. Multivariate Cox regression analysis revealed that CD226 expression on CD8 T cells was an independent prognostic factor (p=0.003) along with CD3 density at invasion margins (p=0.003) and TIGIT expression on CD4 T cells (p=0.019). CD155 was not associated with CD226 prognostic value. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 selectively in liver metastases but not in primary tumors. Down regulation of CD226 on CD8+ infiltrating lymphocytes in liver microenvironment might be restored by IL-15 treatment. CD226 expression on liver metastases-infiltrating CD8+ contributes selectively to the immune surveillance of liver metastases from CRC and displays a prognostic value for patients undergoing radical surgery. Overall design: Liver metastases and paired primary (when available) from 28 patients, treated with chemotherapy, and 10 treatment naïve patients were analyzed with RNAseq