Immune Evasion through HLA-E in Diffuse Large B-Cell Lymphoma: Defining Its Regulation and Cellular Interactions - PROJECT SUMMARY Cancer evolves to evade the immune system through multiple mechanisms, thereby facilitating progression and therapeutic resistance. An emerging escape mechanism is via expression of HLA-E, a non-classical human leukocyte antigen (HLA) class I molecule that can interact with the innate and adaptive immune system. HLA-E is overexpressed in multiple cancers, but how it is uniquely regulated, what antigens are presented in malignancy, and how these influence the interaction with immune cells remains to be determined. To address these questions, diffuse large B-cell lymphoma (DLBCL) is an ideal model because HLA-E is upregulated relative to its normal cell of origin and possesses the highest level of HLA-E expression relative to other tumors. To determine intrinsic regulators of HLA-E, I performed genome-wide CRISPR knockout screens which revealed regulatory factors that uniquely modulate HLA-E relative to other classical HLA class I molecules. My preliminary data suggests that HLA-E can be regulated via a post-transcriptional mechanism that is distinct from classical HLA class I molecules. I will characterize this regulatory mechanism and its functional role using in vitro and in vivo lymphoma models (Aim 1). Additionally, I will determine how presented peptides influence the interaction with immune effector cells in DLBCL by defining the HLA-E peptide repertoire in DLBCL patient derived xenografts and primary tumor biopsies (Aim 2). Finally, I will delineate HLA-E interactions with immune cells in the DLBCL microenvironment (Aim 3). This work will test the overarching hypothesis that HLA-E plays an important role in immune evasion in DLBCL and characterize mechanisms that may tailor future therapeutic approaches. This proposal outlines a five-year plan for Dr. Cynthia Hahn to train in cancer immunology and B cell malignancies. Dr. Hahn is an Instructor in Medicine at Harvard Medical School and Dana-Farber Cancer Institute, a rich intellectual environment with a long track record of training successful physician scientists. She will work under the direct mentorship of Dr. Catherine Wu, a training advisory committee composed of scientific and clinical leaders, and expert collaborators who will work together to facilitate her scientific and career advancement. Dr. Hahn has outlined a thorough career development plan to acquire additional training in cancer biology and immunology, immunopeptidomics, cancer mouse models, and computational biology/biostatistics through coursework, conferences, and collaborations. This training plan will enable Dr. Hahn to successfully achieve her long-term goal of developing an independent research program as a physician scientist investigating tumor- immune interactions and mechanisms of immune evasion in B cell malignancies.
