Immunotherapy has benefitted many patients with previously refractory cancers, but there are still many who do not respond to treatment. The reasons why some patients respond while others do not are complex and incompletely understood, but may depend in part on the level of PD-L1 expression on cancer cells. In order to gain a better understanding of factors influencing PD-L1 levels, Yibin Yang and his group recently profiled how the expression of PD-L1 in anaplastic large cell lymphoma (ALCL) is affected by a panel of genes involved in the ubiquitin-proteasome system. They found that PD-L1 expression is strongly dependent on the E3 ligase KLHL11, which directly binds to and modulates the levels of the transcription factor IRF4.
In this project, they will examine how KLHL11 binds to IRF4, and if the downstream effects on PD-L1 levels are dependent on the activity of the ubiquitin proteasome system and IRF4 chromatin occupancy. They will examine the effect of KLHL11 on ALCL cell survival, cytokine expression, and transcription changes by RNA-seq. To get a better sense of how KLHL11 controls the biology of normal T cell development, they will employ KLHL11 knockout mice. Using these models, they will measure T cell proliferation, cytokine production, and differentiation, both under normal conditions and after an immunization challenge. Gaining a more complete picture of how cancers respond to immunotherapy will lead to better predictions of response, and open avenues for turning non responders into responders by targeting novel pathways.