Germain/Byrne

Project Title

Analysis of the effects of combined anti-CD40 and checkpoint therapy on the tumor microenvironment

NIH Mentor

Ronald N. Germain

Penn Mentor

Katelyn Byrne

Project Details

Pancreatic ductal adenocarcinoma (PDA) is an aggressive and heterogeneous cancer that is often refractory to current treatments. To address this issue, we employ a mouse PDA-derived tumor clone library where individual clones elicit a spectrum of unique immune cell infiltration profiles. We found that a combination of anti-PD1, anti-CTLA-4, and anti-CD40 results in tumor regression in tumor clones with high number of infiltrating T cells, but not those with low numbers. The aim of our study is to gain mechanistic understanding into this therapeutic combination. To that end, we leverage high multiplex microscopy and quantitative image analyses in combination with genetically modified animals, enabling us to decipher the complexities of cellular behaviors, interactions, and phenotypes within an intact TME. Emerging data suggest a central role in effective therapy of agonist CD40 via an IL-12 and IFNg axis, with unexpected contributions from a subset of dendritic cells to the depression of Treg activity in the TME.