Characterization of CD39+CD103+ CD8+ T cells. A, Representative flow cytometry histograms showing the data in B. B, Proportion of CD39− CD103+ (SP CD103), CD39+ CD103+ (DP), and CD39− CD103− (DN) CD8+ T cells expressing PD-1 (n = 36), TIM-3 (n = 36), PD-1-TIM-3 (n = 36), Ki67 (n = 6), and TCF1 (n = 6) in central and peripheral tissues. C, Representative flow cytometry histograms showing the data in D. D, Proportion of DP and DN CD8+ T cells expressing CCR5, CXCR6, CXCR3, CXCR4, and CXCR5 in central and peripheral tissues of 6 patients. E, Representative zebra plots showing the gating strategy for DP CD8+ T cells with high expression of CD39 (CD103+ CD39high) and low expression of CD39 (CD103+ CD39+). F, Proportion of CD103+ CD39+ and CD103+ CD39high expressing PD-1-TIM-3, CCR5, CXCR3, CXCR6, Ki67, and TCF1. F, Left, Representative flow cytometry histograms. Right, Proportion of granzyme B, perforin, and granzyme B-perforin on CD39+ CD103+ DP and CD39− CD103− DN CD8+ T cells from central and peripheral tumor tissues from 7 patients. D and F, Friedman test followed by Dunn test was used to evaluate significant difference between groups. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant. E, 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.
