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V?9V?2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression.

ABSTRACT: V?9V?2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of V?9V?2 T cells in vitro. However, this inclination is often lost in vivo due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of bone marrow (BM) V?9V?2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of V?9V?2 T-cell immune functions which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even in clinical remission after autologous stem cell transplantation. Multiple cell subsets [MM cells, myeloid-derived suppressor cells, regulatory T cells, and BM-derived stromal cells (BMSC)] are involved in V?9V?2 T-cell inhibition via several immune suppressive mechanisms including the redundant expression of multiple immune checkpoints (ICPs). This review will address some aspects related to the dynamics of ICP expression in the BM of MM patients in relationship to the disease status (MGUS, diagnosis, remission, and relapse) and how this multifaceted ICP expression impairs V?9V?2 T-cell function. We will also provide some suggestions how to rescue V?9V?2 T cells from the immune suppression operated by ICP and to recover their antimyeloma immune effector functions at the tumor site.

SUBMITTER: Castella B

PROVIDER: S-EPMC6036291 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Vγ9Vδ2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression.

Castella Barbara B Foglietta Myriam M Riganti Chiara C Massaia Massimo M

Frontiers in immunology 20180625

Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of Vγ9Vδ2 T cells <i>in vitro</i>. However, this inclination is often lost <i>in vivo</i> due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of ...[more]

PMID: 30013559

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Project description:Multiple myeloma (MM) is a lethal B cell neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow and remains incurable due to disease relapse and drug resistance. Bone marrow adipocytes (BMAs) are emerging as playing active functions that can support myeloma cell growth and survival. The aim of this study is to investigate myeloma-mesenchymal stem cells (MSCs) interaction and the impact of such interactions on the pathogenesis of MM using in vitro co-culture assay. Here we provide evidence that MM cell up-regulated MSCs to express PPAR-γ and pushes MSCs differentiation toward adipocytes at the expense of osteoblasts in co-culture manner. The increased BMAs can effectively enhance MM cell to proliferation, migration, and chemoresistance via cell-cell contact and/or cytokines release regulated by PPAR-γ signal pathway. This effect was partially reversed in medium containing PPAR-γ antagonist G3335 and indicated that G3335 distorts the maturation of MSC-derived adipocytes and cytokines release by adipocytes through inhibition of PPAR-γ, a key transcriptional factor for the activation of adipogenesis, or cell to cell contact, or both. In meantime, we observed higher expression of adipocyte differentiation associated genes DLK1, DGAT1, FABP4, and FASN both in MSCs and MSC derived adipocytes, but the osteoblast differentiation-associated gene ALP was down regulated in MSCs. These finding mean that direct consequence of MM/MSC interaction that play a role in MM pathogenesis. Consistent with those in vitro results, our primary clinical observation also showed that bone marrow samples from MM patients had significantly higher bone adiposity in comparison with controls and the number of adipocytes decreased in those who were response to anti-MM therapy. Our finding suggested that BMAs may have an important contribution to MM progression, particularly in drugs resistant of MM cells, and plays an important contribution in MM bone disease and treatment failure, but more clinical studies are needed to confirm its role.

Dataset Information

V?9V?2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression.

Publications

Vγ9Vδ2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression.

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