Proportion of immune cells in pancreatic tissues. The proportion of different immune subsets were studied by flow cytometry in central tissues (CT; blue), peripheral tissues (PT; purple), non-tumor tissues (NTT; brown), and patients’ PBMCs (black). A, Tumor and reactive stroma area calculated by QuPath in the three tissue compartments (n = 9). B, Total numbers of CD4+ and CD8+ T cells per mg of tissue (n = 40). C, Frequency of CD4+ and CD8+ T cells from CD45+ cells (CT, PT n = 35, NTT n = 25, blood n = 35). D, Memory phenotype of CD4+ and CD8+ T cells (CT n = 15, PT n = 14, NTT n = 6, blood n = 24). E, Proportion of CD69 on CD4+ and CD8+ T cells (CT n = 12, PT n = 11, NTT n = 5, blood n = 12). F, Proportion of ICOS on CD4+ and CD8+ T cells (CT n = 15, PT n = 14, NTT n = 5, blood n = 15). G, Proportion of granzyme B, perforin, and granzyme B-perforin coexpression on CD4+ and CD8+ T cells from central and peripheral tumor tissues, non-tumor tissues and patients’ PBMCs (n = 8). H, Proportion of MAIT cells from CD3+ T cells (CT n = 21, PT n = 20, NTT n = 13, blood n = 21). I, Proportion of CD19+ B cells from CD45+ cells (CT n = 32, PT n = 32, NTT n = 26, blood n = 32). A–C, F–I, Friedman test followed by Dunn test was used to evaluate significant difference between groups (CT, PT, NTT; F–I) and patients’ PBMCs if n > 5. *, 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.
