CD8+ T cells selectively detect and eradicate cancer cells. However, tumor infiltrating lymphocytes become dysfunctional (or exhausted) over the course of tumorigenesis, leading to cancer evasion to the immune response.
T cells express distinct profiles of exhaustion in response to a persistent antigen (as observed in autoimmunity, chronic viral infection, cancer,…). How the tumor microenvironment specifically contributes to the irreversible dysfunction (or “terminally exhaustion”) of tumor infiltrating T lymphocytes is still poorly described. Hence, a better understanding of the transcriptional, epigenetic, and metabolic changes underlying tumor-driven T cell exhaustion is mandatory for the rationale design of effective immunotherapies.
To study antitumoral responses during initiation of precancerous lesions and against established tumors, we recently developed a model of autochthonous hepatocarcinoma based on hydrodynamic transfection of mice with a set of oncogenes expressing plasmids and ovalbumin (OVA) as a surrogate tumor-specific antigen. Hydrodynamic injection of a set of mice with ovalbumin-expressing plasmid in the absence of oncogenes drives its expression in non-transformed (healthy) hepatocytes. Transfer of OVA-specific T lymphocytes in these groups of mice allow us to follow antigen-specific T cell fate in response to the same antigen in the context of healthy, precancerous, or advanced hepatocarcinoma liver environment. Our goal is to understand when and how tumor-specific T cells differentiate towards dysfunctional states during tumorigenesis.