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

Abstract

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 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) Vγ9Vδ2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of Vγ9Vδ2 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 Vγ9Vδ2 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 Vγ9Vδ2 T-cell function. We will also provide some suggestions how to rescue Vγ9Vδ2 T cells from the immune suppression operated by ICP and to recover their antimyeloma immune effector functions at the tumor site.

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression

“…Consequently, a decreased MDSC migration reduced the in situ immunosuppression enhancing the T cell-mediated immunity against malignant cells. 38,39 We found that JAM-A overexpression in MMECs strongly correlated with ADAMTS1, a regulator of angiogenesis 40 and immune-surveillance 41 , which appears to play a central role in preparing a favorable BM milieu. 42 We also identified that JAM-A surface expression on MMECs inversely correlated with ADAM17 expression.…”

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

“…Together with a decreased proliferation, this phenotype may explain the marked reduction in tumor growth in animals treated with NZ and doxorubicin. The increased tumor-infiltration of Vγ9Vδ2 T-cells achieved by NZ should be considered as the starting point for designing new strategies of adoptive immune-therapy for osteosarcoma, as already experimented in clinical trials for other tumors [56], in particular, if refractory to the anti-tumor immune activity of CD8 + T-lymphocytes. We did not detect any changes in CD4 + and CD8 + T-lymphocytes infiltrating the tumors upon the treatment with NZ, suggesting a peculiarity of the drug for γδ T-cells.…”

Phase II Trial of Maintenance Treatment With IL2 and Zoledronate in Multiple Myeloma After Bone Marrow Transplantation: Biological and Clinical Results

“…This further supports the idea that γδ lymphocytes can exert antitumor activity and suggests the presence of an inhibition of this phenomenon in multiple myeloma patients. Indeed, it is known that myeloma cells actively remodel the bone marrow microenvironment to establish a protective niche to evade immune control and promote cell growth ( 39 ).…”