Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided “immune-hot” colorectal cancers

Introduction: Characterization of the tumour immune infiltrate (notably CD8+ T-cells) has strong predictive survival value for cancer patients. Quantification of CD8 T-cells alone cannot determine antigenic experience, as not all infiltrating T-cells recognize tumour antigens. Activated tumour-specific tissue resident memory CD8 T-cells (T_RM) can be defined by the co-express of CD103, CD39 and CD8. We investigated the hypothesis that the abundance and localization of T_RM provides a higher-resolution route to patient stratification. Methods: A comprehensive series of 1000 colorectal cancer (CRC) were arrayed on a tissue microarray, with representative cores from three tumour locations and the adjacent normal mucosa. Using multiplex immunohistochemistry we quantified and determined the localization of T_RM. Results: Across all patients, activated T_RM were an independent predictor of survival, and superior to CD8 alone. Patients with the best survival had immune-hot tumours heavily infiltrated throughout with activated T_RM. Interestingly, differences between right- and left-sided tumours were apparent. In left-sided CRC, only the presence of activated T_RM (and not CD8 alone) was prognostically significant. Patients with low numbers of activated T_RM cells had a poor prognosis even with high CD8 T-cell infiltration. In contrast, in right-sided CRC, high CD8 T-cell infiltration with low numbers of activated T_RM was a good prognosis. Conclusion: The presence of high intra-tumoural CD8 T-cells alone is not a predictor of survival in left-sided CRC and potentially risks under treatment of patients. Measuring both high tumour-associated T_RM and total CD8 T-cells in left-sided disease has the potential to minimize current under-treatment of patients. The challenge will be to design immunotherapies, for left-sided CRC patients with high CD8 T-cells and low activate T_RM,that result in effective immune responses and thereby improve patient survival.