The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention

Luu, Khang; Shao, Zhe; Schwarz, Herbert

doi:10.1002/jlb.2mr1119-224r

Cited by 27 publications

(44 citation statements)

References 74 publications

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“…Interestingly, the costimulatory molecule CD137 is also low in R patients. This protein, which acts as a T cell activator and membrane-bound molecule, in soluble form, prevents the activation of T cells and the maturation of antigen-presenting cells such as dendritic cells [25].…”

Section: Sics Are Differently Modulated According To Ecog Ps Scalementioning

confidence: 99%

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

Zizzari

Filippo

Scirocchi

et al. 2020

JPM

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Patients with non-small cell lung cancer (NSCLC) have been shown to benefit from the introduction of anti-PD1 treatment. However, not all patients experience tumor regression and durable response. The identification of a string of markers that are direct or indirect indicators of the immune system fitness is needed to choose optimal therapeutic schedules in the management of NSCLC patients. We analyzed 34 immuno-related molecules (14 soluble immune checkpoints, 17 cytokines/chemokines, 3 adhesion molecules) released in the serum of 22 NSCLC patients under Nivolumab treatment and the gut metabolomic profile at baseline. These parameters were correlated with performance status (PS) and/or response to treatment. Nivolumab affected the release of soluble immune checkpoints (sICs). Patients with a better clinical outcome and with an optimal PS (PS = 0) showed a decreased level of PD1 and maintained low levels of several sICs at first clinical evaluation. Low levels of PDL1, PDL2, Tim3, CD137 and BTLA4 were also correlated with a long response to treatment. Moreover, responding patients showed a high proportion of eubiosis-associated gut metabolites. In this exploratory study, we propose a combination of immunological and clinical parameters (sICs, PS and gut metabolites) for the identification of patients more suitable for Nivolumab treatment. This string of parameters validated in a network analysis on a larger cohort of patients could help oncologists to improve their decision-making in an NSCLC setting.

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Section: Sics Are Differently Modulated According To Ecog Ps Scalementioning

confidence: 99%

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

Zizzari

Filippo

Scirocchi

et al. 2020

JPM

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“…Results from a mouse model of CD showed that treatment with anti-4-1BB monoclonal antibodies seemed to have an anti-inflammatory effect in the colon and increased proportions of splenic CD8 + T cells (32). Interestingly, we observed decreased levels of 4-1BB in serum in patients with active LC compared to controls and it is possible that the soluble form of 4-1BB can act as a decoy molecule and then instead have an inhibitory effect (33). APRIL (a proliferation-inducing ligand) and BAFF (B cell activating factor), expressed on myeloid cells, are involved in the differentiation and survival of B cells (34).…”

Section: Discussionmentioning

confidence: 60%

Patients With Microscopic Colitis Have Altered Levels of Inhibitory and Stimulatory Biomarkers in Colon Biopsies and Sera Compared to Non-inflamed Controls

et al. 2021

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Introduction: Microscopic colitis (MC) is an inflammatory bowel condition with two subtypes, lymphocytic colitis (LC) and collagenous colitis (CC). Unlike patients with ulcerative colitis (UC) and non-inflamed individuals, MC patients have reduced risk of developing colorectal cancer, possibly due to increased immune surveillance in MC patients.Aim: To examine differences in levels of immunomodulatory molecules, including those involved in immune checkpoint mechanisms, in sera from patients with MC and in colonic biopsies from patients with MC and UC compared with controls.Methods: Using Luminex, 23 analytes (4-1BB, 4-1BBL, APRIL, BAFF, BTLA, CD27, CD28, CD80, CTLA-4, E-cadherin, Galectin-3, GITR, HVEM, IDO, IL-2Rα, LAG-3, MICA, MICB, PD-1, PD-L1, PD-L2, sCD40L and TIM-3) were studied in serum from patients with active MC (n = 35) and controls (n = 23), and in colonic biopsies from patients with active LC (n = 9), active CC (n = 16) and MC in histological remission (LC n = 6, CC n = 6), active UC (n = 15) and UC in remission (n = 12) and controls (n = 58).Results: In serum, IDO, PD-1, TIM-3, 4-1BB, CD27, and CD80 were decreased whereas 4-1BBL and IL-2Rα were increased in MC patients compared with controls. In contrast, in biopsies, levels of PD-L2 and 4-1BB were increased in MC and UC patients with active disease. Furthermore, in biopsies from CC and UC but not LC patients with active disease, CTLA-4, PD-1, APRIL, BAFF, and IL-2Rα were increased compared with controls. PD-L1 was increased in CC but not UC or LC patients. CD27 and TIM-3 were decreased in biopsies from MC patients in comparison to controls whereas levels of MICB were decreased in patients with active UC compared with controls.Conclusions: Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.

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“…In particular, the levels of sCD137 and sCD28 during anti-PD-1 treatment resulted signi cantly enhanced. CD137 and CD28 are known as costimulatory receptors but previous studies have shown that their soluble forms have an inhibitory role in immune response [30,31].…”

Section: Discussionmentioning

confidence: 99%

Immune Profile Of Uveal Melanoma Patients: Impact On Clinical Outcome

Rossi

Zizzari

Filippo

et al. 2021

Preprint

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Background. Immunotherapy represents a common therapeutic option for metastatic uveal melanoma, despite the low activity. Although overall survival is often dismal, long survivors can be observed. In this study, the prognostic role of the soluble isoforms of immunomodulatory receptors and cytokines/chemokines was evaluated as well as their ability to identify patients who can benefit more from anti-PD-1 therapy. Methods. Sera from 22 metastatic uveal melanoma patients were assayed to evaluate the levels of cytokines/chemokines and soluble immune checkpoint molecules by multiplex immunoassay analysis. The changes of these molecules during anti-PD-1 therapy were assessed. The correlation between soluble isoforms of immunomodulatory receptors/cytokines/chemokines and survival was analysed. A comparison between circulating immune profile of metastatic uveal melanoma and cutaneous melanoma during anti-PD-1 therapy was also performed. Results. The levels of sCD137, sCD28, sPD-1, sPD-L2 sLAG3, sCD80 and sTim3 were significantly enhanced during anti-PD-1 treatment. Similarly, the levels of IP-10, CCL2 and IDO activity were significantly increased during anti-PD-1 therapy. HVEM, IL-8 and IDO activity were higher in patients with survival < 6 months. Considering these 3 molecules, we obtained a score able to predict patients’ survival. Serum CD137, sGITR and sCD27 were significantly lower in patients with survival > 30 months. Serum GITR, sCD27, sPD-1, sCD80, IFNγ and IDO activity were significantly higher in uveal melanoma patients than in cutaneous melanoma patients during anti-PD-1 therapy. Conclusions. The molecules detected in uveal melanoma during anti-PD-1 treatment reflect the poor activation of immune system and may justify the limited response to immune checkpoint inhibitors. Nevertheless, some patients with metastatic uveal melanoma had a long survival. These patients could be identified through a score based on circulating immune molecules such as HVEM, IDO and IL-8. The comparison of immune profile during anti-PD-1 therapy between uveal melanoma and cutaneous melanoma reflects the different efficacy of immune checkpoint inhibitors in these diseases.

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The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention

Cited by 27 publications

References 74 publications

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

Patients With Microscopic Colitis Have Altered Levels of Inhibitory and Stimulatory Biomarkers in Colon Biopsies and Sera Compared to Non-inflamed Controls

Immune Profile Of Uveal Melanoma Patients: Impact On Clinical Outcome

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