Exosomes Represent an Immune Suppressive T Cell Checkpoint in Human Chronic Inflammatory Microenvironments

Abstract

Background: T cells present in chronic inflammatory tissues such as nasal polyps (from chronic rhinosinusitis patients) have been demonstrated to be hypo-responsive to activation via the TCR, similar to tumor-specific T cells in multiple different human tumor microenvironments. While immunosuppressive exosomes have been known to contribute to the failure of the tumorassociated T cells to respond optimally to activation stimuli, it is not known whether they play a similar role in chronic inflammatory microenvironments. In the current study, we investigate whether exosomes derived from chronic inflammatory microenvironments contribute to the immune suppression of T cells.Methods: Exosomes were isolated by ultracentrifugation and characterized by size and composition using nanoparticle tracking analysis, scanning electron microscopy, antibody arrays and flow exometry. Immunosuppressive ability of the exosomes was measured by quantifying its effect on activation of T cells, using nuclear translocation of NFκB as an activation endpoint.Results: Exosomes were isolated and characterized from two different types of human chronic inflammatory tissues -nasal polyps from chronic rhinosinusitis patients and synovial fluid from rheumatoid arthritis patients. These exosomes arrest the activation of T cells stimulated via the TCR. This immune suppression, like that which is seen in tumor microenvironments, is dependent in part upon a lipid, ganglioside GD3, which is expressed on the exosomal surface. Conclusion:Immunosuppressive exosomes present in nonmalignant chronic inflammatory tissues represent a new T cell checkpoint, and potentially represent a novel therapeutic target to enhance the response to current therapies and prevent disease recurrences.

When Little Things Make a Big Difference

“…The authors also show that blocking the cytokine IL-10, the immune checkpoint PD-L1, or both using monoclonal antibodies can reverse exosome-mediated immunosuppression. These two articles (Shenoy et al 2020 andShu et al 2020), along with many others published before, clearly demonstrate the role of exosomes in disease progression thereby establishing them as a therapeutic target, while offering possible strategies to target them. The article by Shu et al also showcases advances in technology for the detection and quantification of total and specific subsets of exosomes (such as those expressing PD-L1), which have come a long way since the initial discovery of these vesicles.…”

“…The authors report that these exosomes protect macrophages from death mediated by Cisplatin-a chemotherapeutic agent used in cancer treatment, by arresting their proliferation, providing a classic example of the yin-yang effects of exosomes. The second article by Shenoy et al (Shenoy et al 2020) reports a study on exosomes derived from tissues associated with chronic inflammatory diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP) and rheumatoid arthritis. The authors identify exosomes as an immune checkpoint that arrests T cell function, thus possibly contributing to the pathology of these chronic inflammatory diseases.…”

Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments

“… 6 This makes PS an attractive target to neutralize in order to enhance immune responses in cancer, and possibly also in chronic inflammatory conditions, where a similar role for PS+ exosomes has been described. 30 Initial proof-of-concept studies showed that anti-PS antibody could reverse tumor exosome-mediated immunosuppression significantly. 6 Strategies to block PS in preclinical studies using anti-PS antibodies and annexin V or to treat lung cancer in clinical trials using a PS specific antibody, bavituximab, 23 have met with modest success, perhaps due to the relatively low PS-binding affinity of the molecules used and the relatively high molecular weight of the antibody.…”

Preclinical evaluation of cancer immune therapy using patient‐derived tumor antigen‐specific T cells in a novel xenograft platform

“…We plan to overcome this by generating additional tumor target cells derived from the patient's tumor in the future. We also plan to investigate the role of additional immune checkpoints such as other exhaustion markers (CTLA‐4, Tim‐3 and CD160), tumor‐associated exosomes 38–40 as well as exosome‐associated immunosuppressive lipids such as phosphatidylserine 41 and ganglioside GD3 42,43 in the observed tumor escape in future studies. The efficacy of checkpoint blockade can also be enhanced many fold with combination therapy, which can be tested rapidly in our model.…”