Investigating EZH2 Inhibition in Treating Neuroblastoma by CAR T Immunotherapy
Mentor Name: Yael Mosse
My proposed project focuses on the impact of EZH2 inhibition on major histocompatibility complex
class I (MHC-I) expression and immunotherapy efficacy. It has previously been shown that EZH2 inhibition
decreases neuroblastoma proliferation and in vivo tumor growth (Bownes LV, Williams AP, Marayati R, et al.,
PLOS One, 2021.) High-risk neuroblastoma is characterized as a “cold tumor” due to low MHC-I expression
and low mutational burden and are thus resistant to recognition by the immune system.
The goal of this project is to investigate EZH2 inhibition as a method to overcome tumor immune
evasion through enhanced recognition by cell-based therapies. I aim to increase the amount of MHC
expression on the neuroblastoma cell surface using EZH2 inhibition. EZH2 is an enzyme involved in epigenetic
modification, and its expression in cancer cells inhibits T-cell activation by suppressing the MHC-I antigen
presentation pathway. The first aim of my project is to treat cell lines with inhibitors specific for EZH2
methyltransferase (like Tazemetostat) and assess the impact that this has on their growth, viability, MHC-I
expression, and antigen presentation.
The overarching goal of my research is to contribute to the understanding of the immunobiology of
neuroblastoma and determine whether therapies targeting epigenetic modifiers reduce immune escape.
Furthermore, as most pediatric cancers can be classified as “cold tumors” these results could be clinically
relevant to solid pediatric tumors beyond neuroblastoma. Ultimately, a treatment of this kind may lead to longterm
cancer-free survival for patients.
