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posted on 2024-02-19, 14:20 authored by Laia Gorchs, Carlos Fernández-Moro, Ebba Asplund, Marlies Oosthoek, Martin Solders, Poya Ghorbani, Ernesto Sparrelid, Elena Rangelova, Matthias J. Löhr, Helen Kaipe <p>Expression of coinhibitory markers on T cells expressing chemokine receptors. <b>A,</b> Representative flow cytometry zebra plots on CD8<sup>+</sup> T cells showing the gating strategy to identify CCR5, CXCR3, CXCR4, CXCR5, and CXCR6 positive cells. <b>B,</b> Proportion of CCR5 (<i>n</i> = 12), CXCR3 (<i>n</i> = 15), CXCR4 (<i>n</i> = 14), CXCR5 (<i>n</i> = 12), and CXCR6 (<i>n</i> = 6) on CD4<sup>+</sup> and CD8<sup>+</sup> T cells from central and peripheral tumor tissues, non-tumor tissues and patient PBMCs. <b>C,</b> Expression of PD-1, TIM-3, and PD-1-TIM-3 coexpression on CD4<sup>+</sup> and CD8<sup>+</sup> T cells expressing (+) or not (−) CCR5, CXCR3, CXCR4, CXCR5, and CXCR6 in central and peripheral tumor tissues of 6–7 patients. <b>B,</b> Friedman test followed by Dunn test was used to evaluate significant difference between groups. <b>C,</b> Wilcoxon matched pairs signed-rank test was used to detect statistically significant differences. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ns, not significant.</p>
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)
History
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.
