Expression of coinhibitory markers on T cells expressing chemokine receptors. A, Representative flow cytometry zebra plots on CD8+ T cells showing the gating strategy to identify CCR5, CXCR3, CXCR4, CXCR5, and CXCR6 positive cells. B, Proportion of CCR5 (n = 12), CXCR3 (n = 15), CXCR4 (n = 14), CXCR5 (n = 12), and CXCR6 (n = 6) on CD4+ and CD8+ T cells from central and peripheral tumor tissues, non-tumor tissues and patient PBMCs. C, Expression of PD-1, TIM-3, and PD-1-TIM-3 coexpression on CD4+ and CD8+ T cells expressing (+) or not (−) CCR5, CXCR3, CXCR4, CXCR5, and CXCR6 in central and peripheral tumor tissues of 6–7 patients. B, Friedman test followed by Dunn test was used to evaluate significant difference between groups. C, Wilcoxon matched pairs signed-rank test was used to detect statistically significant differences. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.
Funding
Swedish Cancer Foundation
Cancerföreningen i Stockholm (Cancer Society in Stockholm)
Insamlingsstiftelsen Cancer- och Allergifonden (Cancer and Allergy Fund)
Ruth och Richard Julins Stiftelse (Ruth and Richard Julin Foundation)
ARTICLE ABSTRACT
In pancreatic ductal adenocarcinoma, the infiltration of CD8+ T cells within the tumor microenvironment correlates with a favorable prognosis. However, a significant proportion of tumor-infiltrating T cells become trapped within the desmoplastic stroma and lack tumor reactivity. Here, we explored different T-cell subsets in pancreatic tumors and adjacent tissues. We identified a subset of CD8+ T cells, double positive (DP) for CD39 and CD103 in pancreatic tumors, which has recently been described to display tumor reactivity in other types of solid tumors. Interestingly, DP CD8+ T cells preferentially accumulated in central tumor tissues compared with paired peripheral tumor and adjacent non-tumor tissues. Consistent with an antigen encounter, DP CD8+ T cells demonstrated higher proliferative rates and displayed an exhausted phenotype, characterized by elevated expression of PD-1 and TIM-3, compared with CD39−CD103− CD8+ T cells. In addition, DP CD8+ T cells exhibited higher expression levels of the tissue trafficking receptors CCR5 and CXCR6, while displaying lower levels of CXCR3 and CXCR4. Importantly, a high proportion of DP CD8+ T cells is associated with increased patient survival. These findings suggest that DP CD8+ T cells with a phenotype reminiscent of that of tumor-reactive T cells are present in pancreatic tumors. The abundance of DP CD8+ T cells could potentially aid in selecting patients for pancreatic cancer immunotherapy trials.
Patients with pancreatic cancer with a high proportion of CD39+CD103+ CD8+ T cells exhibiting a tumor-reactive phenotype have improved survival rates, suggesting their potential utility in selecting candidates for immunotherapy trials.
