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Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection
Journal article   Open access   Peer reviewed

Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection

Danielle M. Clements, Brenndan Crumley, Glen M. Chew, Elijah Davis, Roberta Bruhn, Edward L. Murphy, Lishomwa C. Ndhlovu and Pooja Jain
Frontiers in immunology, v 12, 608890
09 Mar 2021
DOI: https://doi.org/10.3389/fimmu.2021.608890
PMID: 33767694
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.3389/fimmu.2021.608890View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

HAM HTLV-1 immune checkpoints LAG-3 PD-1 TIGIT TIM-3 TSP Immunology Immunotherapy
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1–5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.

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10 citations in Web of Science
10 citations in Scopus

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Collaboration types
Industry collaboration
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Web of Science research areas
Immunology
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