ABSTRACT Diffuse Large B-cell Lymphoma (DLBCL) is highly associated with HIV and the commonest cause of cancer death among HIV-infected individuals. However, outcomes remain sub-optimal with multiagent chemotherapy. Promising immunotherapies are available, but the tumor-host interactions in DLBCL are poorly understood, even outside the HIV context. Addressing this gap in knowledge is necessary for patient selection, biomarker discovery, and for development of new treatment strategies. However, human studies to date have been limited by the lack available advanced technologies applied to appropriate patient cohorts. Our long-term goal is to improve outcomes for HIV-associated DLBCL by deciphering the diversity, functional heterogeneity, and spatial distribution of effector T-cells within the tumor microenvironment (TME). In this proposal, we utilize DLBCL spontaneously arising in HIV-positive/antiretroviral therapy (ART)-naïve, HIV-positive/ART- experienced, and HIV-negative patients as a comparative model system to investigate the anti-tumor T-cell response on lymphomagenesis. With existing collaborations, our access to a clinically annotated DLBCL sample biocohort from HIV- and ART treated and un-treated HIV+ patients, and advanced technologies, we are in a unique position to characterize and map the T-cell response. To address our goal, we will use highly- multiplexed imaging mass cytometry to characterize the topology of functional T-cell subsets within the TME of DLBCL, perform immune sequencing to study the T-cell receptor (TCR) repertoire characteristics in the TME and peripheral blood, and identify neoantigenic targets using a novel bioinformatic pipeline. The goals of this project are enabled by our existing work in Malawi, where, given the generalized HIV epidemic, comparisons within specific tumor types based on HIV status are uniquely possible. The proposed work is necessary to understand the biological factors underlying lymphomagenesis and improve survival for HIV-associated DLBCL.