Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy

Scott, Gina B.; Carter, Clive; Parrish, Christopher; Wood, Philip; Cook, Gordon

doi:10.1016/j.cellimm.2015.05.002

Cited by 21 publications

(16 citation statements)

References 48 publications

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“…The ICOS/ICOSL signal can mediate helper T‐cell immunity and regulate effector T‐cell differentiation 54 . In vitro , ICOS/ICOSL blockade significantly reduced the generation of MM cell‐induced inhibitory CD4 + Treg cells, 55,56 and lenalidomide, a clinically approved anti‐MM immunomodulatory drug, could inhibit ICOSL expression in MM cells 57 and enhance PD‐1/PD‐L1 blockade‐induced anticancer immunity in MM patients 58 . These evidences, together with our results, underline ICOS/ICOSL blockade as a possible enhancer for anti‐MM immunotherapeutic strategies.…”

Section: Discussionsupporting

confidence: 73%

Identification of the immune checkpoint signature of multiple myeloma using mass cytometry‐based single‐cell analysis

Wang

Zheng

et al. 2020

Clin & Trans Imm

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Objectives New targets or strategies are needed to increase the success of immune checkpoint‐based immunotherapy for multiple myeloma (MM). However, immune checkpoint signals in MM microenvironment have not been fully elucidated. Here, we aimed to have a broad overview of the different immune subsets and their immune checkpoint status, within the MM microenvironment, and to provide novel immunotherapeutic targets to treat MM patients. Methods We performed immune checkpoint profiling of bone marrow (BM) samples from MM patients and healthy controls using mass cytometry. With high‐dimensional single‐cell analysis of 30 immune proteins containing 10 pairs of immune checkpoint axes in 0.55 million of BM cells, an immune landscape of MM was mapped. Results We identified an abnormality of immune cell composition by demonstrating a significant increase in activated CD4 T, CD8 T, CD8+ natural killer T‐like and NK cells in MM BM. Our data suggest a correlation between MM cells and immune checkpoint phenotypes and expand the view of MM immune signatures. Specifically, several critical immune checkpoints, such as programmed cell death 1 (PD‐1)/PD ligand 2, galectin‐9/T‐cell immunoglobulin mucin‐3, and inducible T‐cell costimulator (ICOS)/ICOS ligand, on both MM and immune effector cells and a number of activated PD‐1+ CD8 T cells lacking CD28 were distinguished in MM patients. Conclusion A clear interaction between MM cells and the surrounding immune cells was established, leading to immune checkpoint dysregulation. The analysis of the immune landscape enhances our understanding of the MM immunological milieu and proposes novel targets for improving immune checkpoint blockade‐based MM immunotherapy.

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Section: Discussionsupporting

confidence: 73%

Identification of the immune checkpoint signature of multiple myeloma using mass cytometry‐based single‐cell analysis

Wang

Zheng

et al. 2020

Clin & Trans Imm

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“…The optimal way to address this particular question (ie, abrogation of the immunomodulation produced by lenalidomide with concomitant dexamethasone) would be in a randomized study comparing the immune profiles of patients treated with LenDex vs lenalidomide without dexamethasone. Furthermore, patients enrolled in the observation arm of the QUIREDEX trial also represent an important control group and would have allowed investigation of whether the immune status of treatment-naive high-risk 53 ; alternately, increasing Treg numbers may reflect decreased TNF-a levels after therapy that allow for Treg proliferation. 54 That notwithstanding, we have not found significant differences in Treg numbers between patients with $VGPR vs ,VGPR (data not shown), similarly to that recently reported by Sehgal et al 51 ; accordingly, further translational research in IMiD/dexamethasone-based clinical trials is warranted to fully understand the impact of each drug (separately and in combination) on Tregs.…”

Section: Discussionmentioning

confidence: 99%

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis

Paiva

Mateos

Sánchez‐Abarca

et al. 2016

Blood

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“…In keeping with this mechanism, a previous study has reported that MM patients present a higher percentage of ICOS + cells in follicular helper T cells than healthy controls (56). In an in vitro experiment, ICOS/ICOSL blockade significantly inhibited the generation of MM cell-induced T Reg (CD4 + CD25 + FoxP3 + ) cells (57), and lenalidomide, a clinically verified anti-MM immunomodulatory drug, downregulated ICOSL expression in MM cells (58) and enhanced PD-1/PD-L1 blockade-induced immune response in MM patients (59), underscoring ICOS/ICOSL blockade as a possible anti-MM immunotherapeutic sponsor and enhancer. The fact that large numbers of granulocytes removed by density gradient centrifugation offer the highest expression of PD-L1 and ICOSL highlights the importance of granulocytes in regulating immune-checkpoints.…”

Section: Discussionmentioning

confidence: 80%

Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high‑dimensional single‑cell analysis

Zheng

Zhang

et al. 2020

Oncol Rep

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Immune checkpoint blockade endows patients with unparalleled success in conquering cancer. Unfortunately, inter-individual heterogeneity causes failure in controlling tumors in many patients. Emerging mass cytometry technology is capable of revealing a multiscale onco-immune landscape that improves the efficacy of cancer immunotherapy. We introduced mass cytometry to determine the personalized immune checkpoint status in bone marrow and peripheral blood samples from 3 patients with multiple myeloma, amyloid light-chain amyloidosis, and solitary bone plasmacytoma and 1 non-hematologic malignancy patient. The expression of 18 immune regulatory receptors and ligands on 17 defined cell populations was simultaneously examined. By single-cell analyses, we identified the T cell clusters that serve as immunosuppressive signal source and revealed integrated immune checkpoint axes of individuals, thereby providing multiple potential immunotherapeutic targets, including programmed cell death protein 1 (PD-1), inducible co-stimulator (ICOS), and cluster of differentiation 28 (CD28), for each patient. Distinguishing the cell populations that function as providers and receivers of the immune checkpoint signals demonstrated a distinct cross-interaction network of immunomodulatory signals in individuals. These in-depth personalized data demonstrate mass cytometry as a powerful innovation to discover the systematical immune status in the primary and peripheral tumor microenvironment.

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Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy

Cited by 21 publications

References 48 publications

Identification of the immune checkpoint signature of multiple myeloma using mass cytometry‐based single‐cell analysis

Identification of the immune checkpoint signature of multiple myeloma using mass cytometry‐based single‐cell analysis

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis

Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high‑dimensional single‑cell analysis

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