Project 1: Precision targeting of therapeutic vulnerabilities specific to African American lymphoma patients

PROJECT 1_ Precision targeting of therapeutic vulnerabilities specific to African American lymphoma patients: ABSTRACT Diffuse large B cell lymphomas (DLBCLs) are highly heterogeneous, with many patients remaining incurable, and survivors often facing long-term medical and financial challenges. Patients of African Ancestry (AA) more commonly develop DLBCL at a younger age and have worse outcomes, but little is known about differences in disease biology. Our research found that AA DLBCLs exhibit a unique genetic profile, with mutations in SETD2, ATM, and MGA that impair DNA damage sensing and induce senescence. In AA-DLBCLs and mouse models, we identified an abundance of cells exhibiting the senescence-associated secretory phenotype (SASP), a feature linked to tumor initiation and immune evasion. SASP cells produce distinct cytokines such as IL-16, IL-10, and IL-20. We also observed that most AA-DLBCLs display an inflammatory lymphoma microenvironment (LME) with high levels of exhausted CD8+ T cells – features that predispose to immunotherapy resistance. We hypothesize that AA-DLBCLs represent a novel DLBCL subtype driven by genomic instability and the SASP phenotype, which promotes immune evasion through exacerbated inflammation, possibly driven by IL-16-mediated CD4+ T-cell recruitment and CD8+ T-cell exhaustion. Our proposal will (1) identify the mechanisms driving the SASP phenotype in AA-DLBCLs, (2) uncover how the LME of these tumors promotes immune evasion, and (3) determine the effect of anti-SASP drugs on enhancing immunotherapy and standard-of- care chemotherapy and preventing relapse of AA-DLBCLs.