Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation?

Joseph, Julie; Rahmani, Benjamin; Cole, Yonesha; Puttagunta, Neha; Lin, Edward H.; Khan, Zafar K.; Jain, Pooja

doi:10.1007/s11481-021-10018-3

Cited by 8 publications

(15 citation statements)

References 229 publications

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“…ICs play important roles in implanting immune responses that trigger effector functions in various immune cells (3).…”

Section: Discussionmentioning

confidence: 99%

“…Although sICs significantly impact viral infection (2,3,16), various sICs in patients with SARS-COV-2 infection have not been extensively investigated. Kong et al recently measured 14 sICs in patients with COVID-19 within three days of hospitalization (10), which showed that sIDO, s4-1BB, sTIM-3, and sCD27 were predictive biomarkers of disease severity.…”

Section: Discussionmentioning

confidence: 99%

“…ICs play important roles in implanting immune responses that trigger effector functions in various immune cells ( 3 ). Although sICs significantly impact viral infection ( 2 , 3 , 16 ), various sICs in patients with SARS-COV-2 infection have not been extensively investigated. Kong et al.…”

Section: Discussionmentioning

confidence: 99%

“…Once triggered, these molecules function in either the potent immune response by releasing proinflammatory mediators or by breaking the immune system, maintaining self-tolerance, and preventing immunopathology in the body. In patients with cancer or viral infections, the IC pathway causes T-cell dysfunction to affect immune escape (2)(3)(4)(5)(6). Additionally, IC-targeted treatments have been suggested as alternatives for SARS-CoV-2 infection (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection

et al. 2022

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Coronavirus disease 2019 (COVID-19) has been a pandemic for the past two years. Predicting patient prognosis is critical. Although immune checkpoints (ICs) were shown to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, quantitative studies of ICs in clinical practice are limited. In this study, various soluble ICs (sICs) and cytokine levels in patients with SARS-CoV-2 infection at different time points were compared between survivors and deaths; we also examined whether sICs are useful for predicting prognosis. sICs and cytokines were measured in serum samples from 38 patients diagnosed with COVID-19 in the first and second week post-diagnosis. All assays were performed by bead-based multiplexed immunoassay system using Luminex Bio-Plex 200 system. The correlation of sICs and cytokines with laboratory markers was evaluated, and the levels of sICs in survivors were compared with those in deaths. Among the sICs, the second-week levels of soluble cluster of differentiation (sCD27, p = 0.012), sCD40 (p< 0.001), cytotoxic T-lymphocyte-associated protein 4 (sCTLA-4, p< 0.001), herpes virus entry mediator (sHVEM, p = 0.026), and T-cell immunoglobulin and mucin-domain containing-3 (sTIM-3, p = 0.002) were significantly higher in deaths than in survivors. The levels of nine cytokines assessed in the second week of deaths were significantly higher than those in survivors. The sICs sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines chemokine CC motif ligand 2 (CCL2), GM-CSF, IL-10, and IL-8 showed significant positive correlations with the levels of C-reactive protein (CRP) and procalcitonin and were negatively correlated with the absolute lymphocyte count and platelet values. Increased levels of sICs including sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines were significant factors for poor prognosis. sICs, together with cytokines and inflammatory markers, may be useful as prognostic stratification markers in SARS-CoV-2-infected patients.

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“…ICs play important roles in implanting immune responses that trigger effector functions in various immune cells (3).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection

et al. 2022

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“…ICP molecules can be released in the soluble cell‐free form and presented on the surface of extracellular vesicles (EVs), more so in the context of smaller vesicles (50–300 nm) called exosomes (reviewed in (Joseph et al., 2021 )). Soluble ICP molecules are functional proteins released into the extracellular milieu and can mimic responses similar to their membrane bound isoforms (Joseph et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Retroviral b‐Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation

Joseph

Premeaux

Pinto

et al. 2023

J of Extracellular Bio

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HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <300 nm) while maintaining their immunomodulatory activity. Therefore, we investigated the role of soluble and exosomal ICPs in HTLV-1 associated neuroinflammation. For the very first time, we demonstrate a unique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors in HAM/TSP sera, and in purified exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. These ICPs were found to be co-localized with the endosomal sorting complex required for transport (ESCRT) pathway proteins and exhibited functional binding with their respective ligands. Viral proteins and cytokines (primarily IFNγ) were found to be present in purified exosomes. IFNγ exposure enhanced the release of ICP molecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantly inhibited this process. HTLV-1 b-Zip protein (HBZ) has been linked to factors that enhance EV release and concurrent knockdown here led to the reduced expression of ESCRT associated genes (e.g., Hrs, Vsp, Alix, Tsg) as well as abrogated the release of ICP molecules, suggesting HBZ involvement in this process. Moreso, exosomes from OSP2 cells adversely affected CD8 T-cell functions by diminishing levels of cytokines and cytotoxic factors. Collectively, these findings highlight exosomemediated immunomodulation of T-cell functions with HBZ and ESCRT pathways as an underlying mechanism in the context of HTLV-1-induced neuroinflammation.

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Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy

Sordo-Bahamonde,

Lorenzo-Herrero,

Granda-Díaz

et al. 2023

Mol Cancer

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Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

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Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation?

Cited by 8 publications

References 229 publications

Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection

Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection

Retroviral b‐Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy

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