Tissue-resident memory T Cells in pancreatic ductal adenocarcinoma coexpress PD-1 and TIGIT and functional inhibition is reversible by dual antibody bockade.
Pearce, Hayden Croft, Wayne Nicol, Samantha M Margielewska-Davies, Sandra Powell, Richard Cornall, Richard Davis, Simon J Marcon, Francesca Pugh, Matthew R Fennell, Éanna
Pearce, Hayden
Croft, Wayne
Nicol, Samantha M
Margielewska-Davies, Sandra
Powell, Richard
Cornall, Richard
Davis, Simon J
Marcon, Francesca
Pugh, Matthew R
Fennell, Éanna
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2023-04-03
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
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Pearce H, Croft W, Nicol SM, Margielewska-Davies S, Powell R, Cornall R, Davis SJ, Marcon F, Pugh MR, Fennell É, Powell-Brett S, Mahon BS, Brown RM, Middleton G, Roberts K, Moss P. Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade. Cancer Immunol Res. 2023 Apr 3;11(4):435-449. doi: 10.1158/2326-6066.CIR-22-0121.
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