HIV and Antiretroviral Therapy Influence Tumor Microenvironment Architecture, Subclonal Evolution, and Immune Evasion Strategies in Diffuse Large B-cell Lymphoma.
8 affiliations
- 1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina (UNC), Chapel Hill, North Carolina.
- 2UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
- 3Fischell Department of Bioengineering, University of Maryland, College Park, Maryland.
- 4UNC Project Malawi, Lilongwe, Malawi.
- 5Malawi Ministry of Health, Lilongwe, Malawi.
- 6National Cancer Institute Center for Global Health, Rockville, Maryland.
- 7Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
- 8Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Abstract
The tumor immune microenvironment (TIME) and tumor heterogeneity shape prognosis and therapeutic response in diffuse large B-cell lymphoma (DLBCL), but human immunodeficiency virus (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 pretreatment DLBCL biopsies, stratified by HIV status and antiretroviral therapy (ART) exposure. In IMC, a tumor-immune-hot neighborhood was associated with inferior survival in HIV+ DLBCL (HR = 3.16; P = 0.013). Using ST, HIV+/ART-experienced tumors demonstrated greater macrophage infiltration (P = 0.02) and enrichment for M2 macrophage markers (CD163, MRC1, and 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- tumors, whereas CD58 loss occurred in HIV- tumors only. In an exploratory paired exome subset, high-mutational burden tumors transitioned from proliferative to immune-engaged states, whereas 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 seem 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.Significance
This study demonstrates that the systemic host immunity in which DLBCL arises influences the tumor microenvironment, tumor evolution, and immune evasion strategies that develop, with HIV+ DLBCL exhibiting earlier developmental states and selection for immunosuppressive environments. The findings provide biological rationale for further investigation of checkpoint therapy, and macrophage inhibitors, in HIV-associated lymphomas, despite historic exclusion of this population from immunotherapeutic clinical trials.
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BibTeX
@article{coelho2026antiretroviral,
title = {{HIV and Antiretroviral Therapy Influence Tumor Microenvironment Architecture, Subclonal Evolution, and Immune Evasion Strategies in Diffuse Large B-cell Lymphoma.}},
author = {Jenny Coelho and Sophia M Roush and Samantha Beck and Albert Wielgus and Alexander M Xu and Amon Chirwa and Marriam Mponda and Edwards Kasonkanji and Maurice Mulenga and Tamiwe Tomoka and Satish Gopal and Akil Merchant and Matthew S Painschab and Yuri Fedoriw},
journal = {Cancer research communications},
year = {2026},
month = oct,
doi = {10.1158/2767-9764.crc-26-0343},
url = {https://europepmc.org/article/MED/42831881},
note = {CC BY},
}
RIS
TY - JOUR
TI - HIV and Antiretroviral Therapy Influence Tumor Microenvironment Architecture, Subclonal Evolution, and Immune Evasion Strategies in Diffuse Large B-cell Lymphoma.
AU - Jenny Coelho
AU - Sophia M Roush
AU - Samantha Beck
AU - Albert Wielgus
AU - Alexander M Xu
AU - Amon Chirwa
AU - Marriam Mponda
AU - Edwards Kasonkanji
AU - Maurice Mulenga
AU - Tamiwe Tomoka
AU - Satish Gopal
AU - Akil Merchant
AU - Matthew S Painschab
AU - Yuri Fedoriw
PY - 2026
DA - 2026/10/01
JO - Cancer research communications
DO - 10.1158/2767-9764.crc-26-0343
UR - https://europepmc.org/article/MED/42831881
AB - The tumor immune microenvironment (TIME) and tumor heterogeneity shape prognosis and therapeutic response in diffuse large B-cell lymphoma (DLBCL), but human immunodeficiency virus (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 pretreatment DLBCL biopsies, stratified by HIV status and antiretroviral therapy (ART) exposure. In IMC, a tumor-immune-hot neighborhood was associated with inferior survival in HIV+ DLBCL (HR = 3.16; P = 0.013). Using ST, HIV+/ART-experienced tumors demonstrated greater macrophage infiltration (P = 0.02) and enrichment for M2 macrophage markers (CD163, MRC1, and 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- tumors, whereas CD58 loss occurred in HIV- tumors only. In an exploratory paired exome subset, high-mutational burden tumors transitioned from proliferative to immune-engaged states, whereas 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 seem 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.Significance This study demonstrates that the systemic host immunity in which DLBCL arises influences the tumor microenvironment, tumor evolution, and immune evasion strategies that develop, with HIV+ DLBCL exhibiting earlier developmental states and selection for immunosuppressive environments. The findings provide biological rationale for further investigation of checkpoint therapy, and macrophage inhibitors, in HIV-associated lymphomas, despite historic exclusion of this population from immunotherapeutic clinical trials.
SN - 2767-9764
ER -