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FIGURE 4 from Exhausted Tumor-infiltrating CD39⁺CD103⁺ CD8⁺ T Cells Unveil Potential for Increased Survival in Human Pancreatic Cancer

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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

Tumor-infiltrating CD39⁺CD103⁺ T cells. A, A t-SNE analysis showing cluster point plots (1–8) and sample distribution in central (n = 5) and peripheral (n = 5) tumor tissues on 10-parameters flow cytometry analyses. B, Distribution of each parameter as a single cell level. The color shows the median fluorescence expression (MFI) of each marker. Green circles highlight cluster 3 representing CD4⁺ CD39⁺ T cells. Pink circles highlight cluster 8 representing CD8⁺ CD39⁺ CD103⁺ T cells. C, Heat map showing the distribution of each parameter for every cluster (1–8). The color shows the MFI of each marker (red: high MFI; blue: low MFI). D, Left, Pie charts showing the median values of CD39 SP, DP, CD103 SP, and DN CD4⁺ and CD8⁺ T cells in central tumor tissues (CT) n = 39, peripheral tumor tissues (PT) n = 38, non-tumor tissues (NTT) n = 34 and patient PBMCs (blood; n = 38; right). Flow cytometry dot plots showing the gating strategy to identify CD39⁺ CD103⁻ (CD39 SP), CD39⁺ CD103⁺ (DP), CD39⁻ CD103⁺ (CD103 SP), and CD39⁻ CD103⁻ (DN) on CD8⁺ T cells. Proportion of CD4⁺ T cells SP CD39 (CT n = 39, PF n = 38, NTT n = 34; E) and DP CD8⁺ T cells (F) in CT n = 39 and PF n = 38, NTT n = 34. G, Kaplan–Meier survival curves were performed on patients with high and low frequency of DP CD8⁺ T cells out of CD8⁺ T cells in central, peripheral, and non-tumor tissues. log-rank test was performed to detect statistical significance. H, Forest plots representing survival HRs of the clinicopathologic parameters and DP CD8⁺ T cells in central pancreatic tumor tissues defined in multivariate Cox proportional hazards regression analysis. E 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. T2, Tumor >2 cm; T3, Tumor > 4 cm; T4, Tumor involves coeliac axis, superior mesenteric artery and/or common hepatic artery; N0, No regional lymph node metastasis; N1, Metastases in one to three regional lymph nodes; N2, Metastases in four or more regional lymph nodes; M0, No distant metastasis; M1, Distant metastasis.

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)

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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.

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Keywords

Gastrointestinal Cancers Pancreatic cancer Tumor Microenvironment Immune cells and the microenvironment Immunology T cell exhaustion Immune responses to cancer Immunotherapy Biomarkers for immunotherapy

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FIGURE 4 from Exhausted Tumor-infiltrating CD39+CD103+ CD8+ T Cells Unveil Potential for Increased Survival in Human Pancreatic Cancer