Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets

Abstract

The immune system in cancer patients is normally compromised, as the tumor microenvironment has a drastic effect on immune cell populations, given its ability to promote alternatively activated immune cells. Such immune cells are unable to destroy cancer (initiating) cells, as they are either exhausted or polarized towards an anti-inflammatory profile. Immune checkpoint inhibitors have emerged as a promising strategy to enhance cancer immunotherapy. Anti-PD-1 is of particular interest, as clinical trials have shown its tremendous impact on the immune response due to its capacity of potentiating CD8 T cell functionality. However, the effect of anti-PD-1 treatment on other immune cell populations is largely unknown. Here, we will extensively characterize exhausted CD8 and CD4 T cells, isolated from tissue resections of gastric adenocarcinoma patients, using epigenetic and single cell transcriptomic tolls, as reliable data can be generated with a limited number of cells. This will allow us to discover promising molecular candidates involved in the induction and maintenance of exhausted immune cells within the tumor microenvironment of gastric adenocarcinoma patients. We will further investigate whether these molecular candidates also contribute to the outcome of gastric cancer in functional in vitro immunoassays. Therefore, we will evaluate whether the in vitro inhibition of a particular candidate in combination with anti-PD-1 treatment will improve the antitumoral response of CD8 and CD4 T cells. More importantly, we will assess whether CD19-HLA-DR+ immune cell populations (likely to be plasma cells) act as long-lived antigen presenting cells to sustain a pool of T cells within the gastric tumor microenvironment. We expect to find candidates that, alone or in combination with anti-PD-1 immunotherapy, shape immune cell populations towards a pro-inflammatory profile and consequently facilitate tumor elimination, which will open perspectives for cancer treatment. (AU)