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Research ArticleAIDS/HIVHematology
Open Access | 
10.1172/jci.insight.180771
1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
Find articles by Damania, B. in: JCI | PubMed | Google Scholar
1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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1Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
3University of North Carolina Project Malawi, Lilongwe, Malawi.
4University of Malawi College of Medicine, Lilongwe, Malawi.
5University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
6Department of Pathology, School of Medicine and Oral Health, Kamuzu University of Health Sciences, Lilongwe, Malawi.
7Department of Microbiology and Immunology and
8Division of Hematology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
9Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10National Cancer Institute Center for Global Health, Rockville, Maryland, USA.
Address correspondence to: Yuri Fedoriw, 822 Brinkhous-Bullitt Building, 160 Medical Center Dr., Chapel Hill, North Carolina 27514, USA. Email: yuri.fedoriw@unchealth.unc.edu.
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Published May 23, 2024 - More info
Published in Volume 9, Issue 13 on July 8, 2024
AbstractThe most common subtype of lymphoma globally, diffuse large B cell lymphoma (DLBCL), is a leading cause of cancer death in people with HIV. The restructuring of the T cell compartment because of HIV infection and antiretroviral therapy (ART) may have implications for modern treatment selection, but current understanding of these dynamic interactions is limited. Here, we investigated the T cell response to DLBCL by sequencing the T cell receptor (TCR) repertoire in a cohort of HIV-negative (HIV–), HIV+/ART-experienced, and HIV+/ART-naive patients with DLBCL. HIV+/ART-naive tumor TCR repertoires were more clonal and more distinct from each other than HIV– and HIV+/ART-experienced ones. Further, increased overlap between tumor and blood TCR repertoires was associated with improved survival and HIV/ART status. Our study describes TCR repertoire characteristics for the first time to our knowledge in an African DLBCL cohort and demonstrates contributions of HIV infection and ART exposure to the DLBCL TCR repertoire.
Graphical Abstract
Introduction
HIV infection alters the immune environment through oncogenic viral reactivation, decreased immune surveillance, and persistent immune activation, together contributing to increased risk of cancer, particularly aggressive B cell lymphoma (1). Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma subtype in people with HIV and without HIV (2, 3). Effective antiretroviral therapy (ART) implementation worldwide has led to a growing and aging HIV+ population, such that DLBCL is now a leading cause of cancer death for people with HIV (4–6). Extensive molecular characterization has identified biologically and therapeutically meaningful subtypes of DLBCL, but these studies have excluded DLBCL arising in people with HIV (HIV+ DLBCL) (7–10). The distinct molecular profile of HIV+ DLBCL provides evidence for an impact of HIV on lymphomagenesis and immune response, and elucidating this impact is crucial for improving therapeutic paradigms for HIV+ patients with DLBCL (11, 12).
In the era of immunotherapy, there is interest in understanding tumor-host interactions, particularly in T cells, to improve treatment selection and outcomes for patients with cancer. Naive T cells express a unique T cell receptor (TCR) that results from gene rearrangement in the thymus (13). Upon binding to a peptide antigen presented by major histocompatibility complex (MHC) molecules of a nucleated cell (MHC class I, recognized by CD8+ T cells) or an antigen-presenting cell (MHC class II, recognized by CD4+ T cells), the T cell proliferates to mount an immune response, termed “clonal expansion” (14). TCR repertoire sequencing and the various methods to estimate bulk clonality metrics and predict antigen specificity have been thoroughly reviewed by Frank et al. (13). In brief, high TCR repertoire clonality implies much of a repertoire is composed of relatively few distinct clones that have expanded, while high TCR repertoire diversity results from many different clones in the repertoire. High clonality in the tumor TCR repertoire may indicate effective antitumor T cell response. Meanwhile, in the blood TCR repertoire, high clonality may indicate immune dysfunction (e.g., loss of CD4+ T cells because of untreated HIV) or response to an active infection leading to rapid expansion of select clones.
In HIV– DLBCL, the presence of tumor-infiltrating lymphocytes, likely a consequence of effective tumor targeting and clonal expansion, is associated with improved prognosis (15). TCR repertoires have been investigated to decipher intra- and intertumor immune heterogeneity, which may have implications for biomarker development (13). Tumor and whole-blood TCR repertoire diversity, as well as the degree of overlap between these compartments, have been assessed as predictive and prognostic biomarkers in a variety of solid tumors (16). In a cohort of HIV– patients with DLBCL treated with conventional chemotherapy, higher intratumor TCR repertoire diversity was positively prognostic (17).
In the setting of HIV infection, systemic immune response is dysregulated through a decrease in the CD4+ T cell compartment and chronic stimulation and exhaustion of CD8+ T cells (18). Over time, HIV infection results in decreased TCR repertoire diversity, in part due to an expansion of clones targeting common HIV epitopes during chronic infection (19). Though ART restores T cell function and immune response, patients have varying responses (20–22). Furthermore, the impact of HIV infection and ART exposure on the DLBCL TCR repertoire has not been investigated.
Forming generalizable conclusions regarding antitumor immune responses in HIV+ DLBCL in high-income countries is difficult because of a disproportionate HIV burden on men who have sex with men and racial/ethnic minorities (23). Our cohort offers distinctive opportunities to investigate DLBCL biology by HIV and ART status given the generalized HIV epidemic and effective ART scale-up effort in Malawi, as well as the substantial number of HIV+ and HIV– lymphomas at our site (6). Importantly, our cohort has relatively few EBV+ DLBCLs, allowing us to focus on effects of HIV, rather than EBV, on immune response to tumor (24). In this study, enabled by longstanding clinical research collaboration focused on cancer in a setting with extremely limited public sector health care resources and high HIV prevalence, we aimed to characterize the TCR repertoire of DLBCL under varying degrees of immune pressure.
ResultsPatient characteristics. Our TCR-sequencing cohort consisted of 62 patients, n = 16 (26%) of which had paired tumor and whole blood for analysis (Table 1). The median age was 46 years and the median overall survival (OS) was 14 months. HIV+/ART-naive patients had a median OS of 50 months, compared with 10 months for HIV+/ART-exp. patients and 23 months for HIV– patients. For patients who were HIV+, the median time on ART before DLBCL diagnosis was 36 months (0.2 months for the ART-naive cohort and 58 months for the ART-exp. cohort). The median HIV viral load was 0 copies in HIV+/ART-exp. patients compared with 9,800 copies in HIV+/ART-naive. Among patients, 32% received rituximab with an even distribution across HIV/ART status. All patients had corresponding transcriptomics sequencing data, except for 1 HIV– patient. A total of 30 (48%) tumors were GC type by GEP. The HIV– tumor without gene expression profiling data was predicted to be non-GC type by the Hans algorithm (25). Only n = 6 (10%) tumors were EBV+ by EBER in situ hybridization (ISH). A total of 57 pretreatment DLBCL tumors (n = 19 HIV–, n = 27 HIV+/ART-exp., n = 11 HIV+/ART-naive) and 21 pretreatment whole-blood samples (n = 7 HIV–, n = 7 HIV+/ART-naive, n = 7 HIV+/ART-exp.) from the 62 patients in the cohort were included for TCR sequencing. All patients were followed for up to 5 years or censored at the time of analysis with no loss to follow-up.
Table 1Clinical and immunohistochemical data of sequenced patients
TCR-sequencing output. The median number of total templates was 385 for tumor and 27,000 for blood samples, with a similar percentage of productive templates in each (77% tumor, 80% blood). Further TCR metrics are in Table 2. Only productive templates were considered for the analyses in this manuscript. Because of the difference in median total productive templates (20,700 in blood vs. 300 in tumor), random downsampling to the lowest value above the 100-template threshold (n = 108, averaged over 100 iterations) was performed on all samples with more than 100 productive templates to account for differences in T cell and template input. Thus, further bulk clonality and diversity metric comparisons were not affected by T cell count. Thirty-five tumors (n = 12 HIV–, n = 8 HIV+/ART-naive, n = 15 HIV+/ART-exp.) and 17 whole-blood samples (n = 6 HIV–, n = 7 HIV+/ART-naive, n = 4 HIV+/ART-exp.) met inclusion criteria for clonality analysis (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.180771DS1). Of tumors that met criteria for clonality analysis, 2 were EBV+ by EBER ISH (n = 1 HIV+/ART-exp., n = 1 HIV–).
Table 2Non-downsampled output from TCR sequencing
Tumor TCR repertoires have increased large TCR expansions. We first compared overall TCR clonality by tissue type. Blood TCR repertoires were more clonal (productive Simpson clonality: 1.6-fold, P < 0.001; max productive frequency: 3.6-fold, P < 0.001; Wilcoxon rank sum test) and had fewer unique productive rearrangements (0.78-fold, P < 0.001, Wilcoxon rank sum test) compared with tumor repertoires (Figure 1, A and B). To further investigate the bulk clonality metrics of the repertoire, we classified each clonal expansion based on the proportion of repertoire it occupied (small: 0–0.0001, medium: 0.0001–0.001, large: 0.001–0.01, or hyperexpanded: 0.01–1) without downsampling. Blood TCR repertoires had higher mean proportions of repertoire composed of small expansions (14.8-fold, P < 0.001, Wilcoxon rank sum test) and hyperexpanded clones (3.8-fold, P < 0.001, Wilcoxon rank sum test) compared with tumor. Meanwhile, tumor TCR repertoires had higher mean proportions of repertoire composed of large expansions (2.8-fold, P < 0.001, Wilcoxon rank sum test) than blood TCR repertoires (Figure 1C). Stratifying by size of clonal expansion revealed that blood TCR repertoires were heavily enriched for small expansions, likely representing background immune diversity, with some enrichment for hyperexpanded clones, which could be related to infection or tumor response. Meanwhile, tumor TCR repertoires were characterized by large TCR expansions, potentially indicative of effective antitumor immune response.
Figure 1HIV/ART status is associated with tumor, but not blood, TCR repertoire bulk clonality metrics. (A) Simpson clonality by tissue type (n = 52, Wilcoxon rank sum test). Blood TCR repertoires had higher Simpson clonality compared with tumor. (B) Unique rearrangements by tissue type (n = 52, Wilcoxon rank sum test). Tumor TCR repertoires had more unique rearrangements compared with blood. (C) Relative abundance of TCRs with specific frequencies by sample type (n = 52, Wilcoxon rank sum test). Blood TCR repertoires had more hyperexpanded clones and small expansions compared with tumor, while tumor TCR repertoires had more large expansions. (D) Tumor Simpson clonality by HIV/ART status (n = 35, pairwise Wilcoxon rank sum test). HIV+/ART-naive tumor repertoires were more clonal compared with HIV+/ART-exp. and HIV–. (E) Tumor unique rearrangements by HIV/ART status (n = 35, pairwise Wilcoxon rank sum test). HIV+/ART-naive tumor repertoires had fewer unique rearrangements compared with HIV+/ART-exp. and HIV–. (F) Relative abundance of tumor TCRs with specific frequencies by HIV/ART status (n = 35, Kruskal-Wallis test). HIV+/ART-naive tumor TCR repertoires had more hyperexpanded clones. (G) Blood Simpson clonality by HIV/ART status (n = 17, pairwise Wilcoxon rank sum test). Similar blood TCR repertoire clonality among HIV/ART groups. (H) Blood unique rearrangements by HIV/ART status (n = 17, pairwise Wilcoxon rank sum test). Similar blood TCR repertoire diversity among HIV/ART groups. (I) Relative abundance of blood TCRs with specific frequencies by HIV/ART status (n = 17, Kruskal-Wallis test). Only productive templates were considered. Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). DS indicates metrics were downsampled (A, B, D, and E). Horizontal black line indicates median (A, B, D, E, G, and H).
HIV+/ART-naive DLBCL TCR repertoires are more clonal than HIV+/ART-exp. and HIV– DLBCL. We next tested for associations between bulk TCR repertoire metrics and the following covariates: HIV status, HIV/ART status, age, sex, HIV viral load, CD4+ T count, ART duration, LDH, ECOG score, stage > 2, Ki-67, EBER, and cell of origin. In tumor, only HIV/ART status was associated with bulk TCR repertoire metrics (p.adj = 0.043 for productive Simpson clonality, max productive frequency, and unique productive rearrangements; Kruskal-Wallis test with Benjamini-Hochberg [BH] correction). There was no association between HIV/ART status and total productive template count (P = 0.86; Kruskal-Wallis test with BH correction). In blood, there were no statistically significant associations between clonality metrics and any of the tested covariates.
As it was the only covariate that associated with bulk TCR clonality metrics, we aimed to further investigate the relationship between HIV/ART status and TCR repertoire clonality. Although total productive template count was similar by HIV/ART status, essentially normalizing for any differences in T cell presence in tumor, HIV+/ART-naive tumors had more clonal TCR repertoires than HIV– tumors (productive Simpson clonality: 1.4-fold, P = 0.0096; max productive frequency: 3.1-fold, P = 0.012; unique productive rearrangements: 0.88-fold, P = 0.016; pairwise Wilcoxon rank sum test) and HIV+/ART-exp. (productive Simpson clonality: 1.4-fold, P = 0.019; max productive frequency: 2.5-fold, P = 0.026; unique productive rearrangements: 0.90-fold, P = 0.028; pairwise Wilcoxon rank sum test) (Figure 1, D and E). Interestingly, there was no difference between HIV– and HIV+/ART-exp. tumor clonality. HIV+/ART-naive tumors had a higher proportion of clones that were hyperexpanded compared with HIV+/ART-exp. and HIV– tumors (P = 0.022, pairwise Wilcoxon rank sum test) (Figure 1F). In blood, there were no differences in unique productive rearrangements, productive Simpson clonality, maximum productive frequency, or proportion of clonal expansion by HIV/ART status (Figure 1, G–I). Taken together, tumor TCR clonality, but not blood TCR clonality, was associated with HIV/ART status. HIV+/ART-naive DLBCL TCR repertoires were the most clonal, and ART may restore TCR diversity in HIV+/ART-exp. tumors to be similar to HIV– DLBCL.
High unique productive rearrangements in blood associate with improved survival. HIV status was not associated with OS (P = 0.9, Cox regression, Figure 2A) or progression-free survival (PFS) (P = 0.8, Cox regression) in the entire TCR-sequencing cohort (n = 62 patients). HIV/ART-naive patients trended toward improved OS and PFS compared with patients who were HIV+/ART-exp. (OS: HR = 0.43, P = 0.09; PFS: HR = 0.38, P = 0.054; Cox regression) or HIV– (OS: HR = 0.52, P = 0.2, PFS: HR = 0.47, P = 0.14; Cox regression) (Figure 2B). Tumor TCR repertoire clonality may represent the strength and efficacy of the T cell response, and as such, affect patient outcome. When analyzing HIV+ and HIV– tumors together, none of the clonality metrics associated with OS or PFS (Figure 2C, PFS not shown). When analyzing HIV+ tumors only, increased clonality was associated with improved OS (productive Simpson clonality: HR = 0.30, P = 0.044; max productive frequency: HR = 0.33, P = 0.064; Cox regression) and PFS (productive Simpson clonality: HR 0.25, P = 0.021; max productive frequency: HR = 0.28, P = 0.034; Cox regression) (Figure 2D). These were not significant after adjusting for ART status. When analyzing HIV– tumors only, there was no difference in survival by clonality (P = 0.5, Cox regression) (Figure 2E). We also assessed for associations between blood TCR repertoire clonality metrics and survival. Having a more diverse TCR repertoire in blood correlated with improved OS (unique productive rearrangements: HR = 0.20, P = 0.023, Cox regression) and remained significant after adjusting for age and HIV/ART status (HR = 0.21, P = 0.044, Cox regression) (Figure 2F).
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