Activated regulatory T-cells, dysfunctional and senescent T-cells dominate the microenvironment of pancreatic cancer

Abstract

Pancreatic cancer has the worst prognosis of any human malignancy and lymphocytes appear to be a major prognostic marker of the disease. There is a need to better characterise T-cells of pancreatic cancer in order to identify novel therapeutic strategies. In this study, a multi-parameter analysis of human pancreatic cancer cases revealed three novel characteristics of T-cells. Using a T-cell focused CyTOF panel, we analysed approximately 32,000 T-cells in eight patients. Our observations show a regulatory T-cell population was characterized by a highly immunosuppressive state with high TIGIT and ICOS expression, and the CD8 T-cells were either senescent or exhausted but with lower PD1 levels. These data suggest that the microenvironment of pancreatic cancer is extremely suppressive and could be a major driver of poor prognosis. These findings have been subsequently validated in a large pancreatic cancer single-cell RNA sequencing dataset using 13,000 T cells. This work identifies potential therapeutic targets and avenues that should be further investigated through rational design of clinical trials.

T cells in pancreatic cancer stroma

“…While CD4 + Tregs are a prominent feature of the immune infiltrate, CD8 + T cells are rare in the PDAC microenvironment[ 24 ]. Consequently, PDAC is considered to be a poorly immune responsive cancer, with T cells present within the tumour microenvironment often showing lack of activation, or an exhausted phenotype[ 28 - 30 ]. This observation demonstrates that infiltrated CD8 + T cell may recognise and mount a response against these tumours, but the unfavourable TME halts optimal cytotoxic function.…”

“…A recent study using multiplex immunohistochemistry imaging combined with single-RNA sequencing to evaluate T cell landscape and function in patients with pancreatic cancer, demonstrated that infiltrated CD8 + T cells displayed a senescent phenotype, identified by the expression of CD57 + CD27 - CD28 - or CD45RA + CD27 -/Low CD28 -/Low or an exhausted phenotype with elevated expression of TIGIT + and CD39 + markers alongside PD-1 low/intermediate expression[ 30 ]. Senescent and exhausted T cells as well as Tregs were also identified within the CD4 + population.…”

“…Senescent and exhausted T cells as well as Tregs were also identified within the CD4 + population. Additionally, intra-tumoural Tregs exhibit highly suppressive phenotypes, highlighted by the expression of multiple (TIGIT, ICOS, CD39) inhibitory markers[ 30 ].…”