HIV and Antiretroviral Therapy Influence Tumor Microenvironment Architecture, Subclonal Evolution, and Immune Evasion Strategies in Diffuse Large B-Cell Lymphoma.

Authors

Jenny Coelho, Sophia M Roush, Samantha Beck, Albert Wielgus, Alexander M Xu, Amon Chirwa, Marriam Mponda, Edwards Kasonkanji, Maurice Mulenga, Tamiwe Tomoka, Satish Gopal, Akil Merchant, Matthew S Painschab, Yuri Fedoriw

Published in

Cancer research communications. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

The tumor immune microenvironment (TIME) and tumor heterogeneity shape prognosis and therapeutic response in Diffuse Large B-cell Lymphoma (DLBCL), but HIV-associated (HIV+) DLBCL remains poorly understood. To characterize the TIME and tumor-intrinsic features of DLBCL across a spectrum of HIV-associated immune dysregulation, we applied imaging mass cytometry (IMC), spatial transcriptomics (ST), and whole exome sequencing to 61 pre-treatment DLBCL biopsies, stratified by HIV status and antiretroviral therapy (ART) exposure. By IMC, a tumor-immune hot neighborhood associated with inferior survival in HIV+ DLBCL (HR=3.16, p=0.013). By ST, HIV+/ART-experienced tumors demonstrated greater macrophage infiltration (p=0.02) and enrichment for M2 macrophage markers (CD163, MRC1, MARCO) and PDCD1:CD274 coexpression. Unsupervised clustering identified 17 shared subclonal niches, with PRC1/BMI1 dysregulation in HIV+ tumors and PRC2/EZH2 enrichment in HIV-negative (HIV-) tumors. Pseudotime positioned HIV+/ART-naïve, HIV+/ART-experienced, and HIV- tumors at progressively later transcriptional states. CD47 increased over pseudotime in HIV+/ART-experienced tumors but decreased in HIV-, while CD58 loss occurred in HIV- tumors only. In an exploratory paired exome subset, high-mutational-burden tumors transitioned from proliferative to immune-engaged states, while low-burden tumors accumulated extracellular matrix and myeloid signatures suggesting fibrotic microenvironments. The data define distinct immune architectures in DLBCL across a spectrum of HIV-associated immune dysregulation. HIV and ART exposure appear to shape the DLBCL TIME in a manner that may reflect the degree of immune reconstitution during lymphomagenesis. The immunosuppressive, checkpoint-enriched microenvironment of ART-experienced tumors supports further investigation of immune checkpoint blockade and macrophage-targeting strategies in a population historically excluded from such trials.

PMID:
42831881
Bibliographic data and abstract were imported from PubMed on 05 Oct 2026.

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