Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided “immune-hot” colorectal cancers
Shahd Talhouni, Wakkas Fadhil, Nigel P. Mongan, Lara Field, Kelly J. Hunter, Sogand Makhsous, Alexandre Maciel-Guerra, Nayandeep Kaur, Aušrinė Nestarenkaitė, Arvydas Laurinavičius, Benjamin E. Willcox, Tania Dottorini, Ian Spendlove, Andrew M. Jackson, Mohammad Ilyas, Judith M. Ramage
Abstract
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.