Coinhibitory receptor expression on CD4+ and CD8+ tumor-infiltrating T cells. Proportion of CD4+ (A) and CD8+ (B) T cells expressing PD-1 (CT n = 54, PT n = 52, NTT n = 42), TIM-3 (CT n = 53, PT n = 51, NTT n = 41), LAG-3 (NTT n = 6, CT n = 16, PT n = 16), CTLA-4 (CT n = 9, PT n = 8,NTT n = 2), and coexpressing PD-1 and TIM-3 coinhibitory markers (CT n = 53, PT n = 51, NTT n = 41; C, left), flow cytometry representative dot plots on CD8+ T cells (right) to identify coexpression of PD-1 and TIM-3. D, Proportion of PD-1, TIM-3, PD-1TIM-3, LAG-3, and CTLA-4 in CD4+ and CD8+ T cells from patients’ PBMCs. E, Boolean gating analysis was performed on TIM-3, PD-1, and LAG-3 (n = 16). Pies (left) show median values on central tumor tissues (CT), peripheral tumor tissues (PT), and patients’ PBMCs (blood). F, Proportion of CD4+ and CD8+ T cells expressing 0, 1, 2, or 3 coinhibitory markers in central and peripheral tumor tissues. A–C, Friedman test followed by Dunn test was used to evaluate significant difference between groups (CT, PT, NTT) if n > 5. E, Wilcoxon matched pairs signed-rank test was used to detect statistically significant differences between CT and PT tissues. *, 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.
