Abstract 9P
Background
Tissue-resident memory (TRM) T cells have emerged as key players in cancer immunosurveillance, and their presence has been linked to a favorable clinical outcome in solid cancer patients. Liver metastases exhibit a highly immunosuppressive tumor microenvironment, however, the role and clinical impact of TRM cells infiltration in colorectal cancer remains elusive.
Methods
An exhaustive profiling was conducted on tumor-infiltrating lymphocytes isolated from 27 patients’ colorectal cancer (CRC) liver metastases. Cytokine production was evaluated in in vitro-activated TRM and non-TRM cells. 3D spheroid models were also used to study CXCR6+/- TRM cells cytotoxicity. Prognostic value of TRM cells was assessed. Single-cell RNAseq data were analyzed to investigate the transcriptomic profile of TRM cells subsets.
Results
Our analyses showed that only infiltration with CD103+CD69+ TRM cells was predictive of recurrence-free survival (RFS). However, CXCR6 expression on this TRM subset helped to stratify this population’s prognostic impact and was associated with shorter RFS. CXCR6 expression was inversely correlated to PD-1, HLA-DR, and CD39 expression, three well-validated biomarkers of tumor-reactive T cells. Strikingly, the expression of PD-1 in this TRM population was associated with improved patients’ prognosis. Interestingly, both in vitro and single-cell RNAseq data analyses revealed that CXCR6-PD1+ TRM cells showed significantly lower levels of TIM3 and LAG3 expression compared to CXCR6+PD1- that could be explained by a non-terminal exhausted state. Although both TRM populations presented high production levels of IFNg, GZMB, and IL-2; CXCR6-PD1+ TRM cells produced higher levels of TNFa. We next assessed TCF1 and TOX expression. Interestingly, CXCR6+PD1- TRM cells were more TCF1-TOX+, contrarily to CXCR6-PD1+ TRM cells that were more stem-like ‘TCF1-TOX+’. Finally, CXCR6-PD1+ TRM cells showed a significant increase in Ki67 expression.
Conclusions
We identified a novel population of TRM cells CXCR6-PD1+ that exhibit a ‘stem-like’ phenotype with higher proliferation capacity and are associated with improved prognosis in metastatic CRC patients.
Legal entity responsible for the study
UMR RIGHT 1098.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
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