MYCN drives a suppressive tumor immune microenvironment in neuroblastoma.

PROJECT SUMMARY Amplification of the oncogene MYCN drives high-risk progressive disease, resistance to therapy, and a poor overall survival rate below 45% for high-risk neuroblastoma (NB) patients. Further, more than half of all high-risk patients will relapse, and the post-relapse survival rate is only 10%. MYCN-driven NB tumors are characterized by low mutational load, low MHC-I expression, reduced immune cell infiltration, and impaired T cell effector functions. As a result, MYCN-amplified NB is immunologically quiescent, thus limiting immunotherapy approaches. This proposal addresses a major obstacle to developing effective therapies for MYCN-amplified NB by delineating the molecular mechanisms through which MYCN drives T cell dysfunction and thus a suppressive tumor immune microenvironment (TIME). Based on our data and the recent literature, our guiding hypothesis is that MYCN reprograms T cell metabolism to drive an immune suppressive TIME. Specifically, we hypothesize that MYCN creates a lipid-rich tumor microenvironment that benefits NB growth and impairs T cell effector functions. This proposal will (1) determine how MYCN rewires T cell metabolism to drive immune suppression; and (2) elucidate how MYCN-induced de novo lipogenesis contributes to a suppressive TIME. Deciphering how MYCN contributes towards a suppressive TIME is vital for developing new and improved immunotherapy strategies for high-risk NB.