Our current understanding of immune surveillance of cancer is colored by the ‘immunoediting hypothesis’ which posits that the immune system suppresses the expansion of nascent cancers by identifying and eliminating cancer cells that express potent neoantigens. Thus, via immune surveillance the repertoire of neoantigens are sculpted, such that tumors eventually evade immune detection altogether because the remaining neoantigens are insufficiently immunogenic. During immune checkpoint therapy (ICT) it is believed that these neoantigens that were not previously acted upon by the immune system are now sufficiently potent to promote immune-mediated destruction of cancer cells due to a lowered immunogenicity threshold. Therefore, the immunogenicity threshold is a critical predictor of immune surveillance during nascent stages of cancer evolution and for the efficacy of ICT. However, the nature of the immunogenicity threshold is poorly defined but almost certainly impacted by cancer cell intrinsic alterations that extend beyond the specific neoantigens. The central hypothesis of this project is that activation of select oncogenes or inactivation of select tumor suppressor genes contributes to defining the immunogenicity threshold, cancer cell immune evasion, and the efficacy of ICT. Thus, the genotype of cancer cells will affect the overall immunogenicity threshold such that a given antigen, or set of antigens, will elicit an immune response in one genetic context but not in another. This hypothesis challenges our current assumptions regarding the immunoediting hypothesis and provides an alternative lens through which we must approach the etiology of cancer progression and the response to ICT.

In this project, we employ in vivo somatic cell engineering and high-throughput in vivo screens to uncover the molecular underpinnings of tumor immune surveillance. Please contact David to learn more about joining this team.