T cell regulation in pancreatic ductal adenocarcinoma

Background:

Pancreatic cancer has the worst prognosis of any human malignancy. We have shown using transcriptomics and histopathology that immune infiltrate in resection samples from a whipple’s operation is predictive of prognosis. In particular, lymphocytes appear to be a major prognostic marker. With promising immunotherapies being proposed for other cancers, there is a need for a deeper understanding of the immune landscape of pancreatic cancer to identify points of intervention.

Methods:

We have developed a 37-marker mass cytometry staining panel to characterise the dominant immune populations within primary pancreatic cancer. Our panel further analyses T-cell subpopulations and their functional status including a host of clinically relevant checkpoint markers and immunosuppressive signatures.

Results:
The degree of immune infiltration we observe is highly variable between patients, but all patients equivocally show a complex immune microenvironment consistent of macrophages, neutrophils and different lymphocytes. The T-cells infiltrating the tumour, both CD4 and CD8 T-cells, appear to be dysfunctional with hardly any activation signature. A highly suppressive phenotype also characterises the regulatory T-cell population. Our data suggest that the microenvironment of pancreatic cancer is extremely suppressive and could be a major driver of poor prognosis. Yet, this work identifies potential therapeutic targets and avenues that should be further investigated and may inspire future clinical trials.

Future Work:

We are planning to investigate the behaviour of T-regs from PDAC using in-vitro assays. To that end, we will use a recently developed advanced 3D culture system to visualise their interactions with CD8s and the functional consequences of those interactions on CD8 mediated killing.