A clinical trial of adoptively transferred activated V9V2 T cells in combination with ZA and IL-2 was well tolerated, but showed very limited clinical efficacy (9)

A clinical trial of adoptively transferred activated V9V2 T cells in combination with ZA and IL-2 was well tolerated, but showed very limited clinical efficacy (9). in the BM of MM patients in relationship to the disease status (MGUS, diagnosis, remission, and relapse) and how this multifaceted ICP expression impairs V9V2 T-cell function. We will also provide some suggestions how to rescue V9V2 T cells from the immune suppression operated by ICP and to recover their antimyeloma immune effector functions at the tumor site. TCR in association with the isoform A1 of the butyrophilin-3 (BTN3A1) protein family (3, 4). IPP is usually structurally related to the phosphoantigens generated by bacteria and stressed cells that are patrolled by V9V2 T cells as part of their duty to act as first-line defenders against infections and stressed cell at risk of malignant transformation (5). One strategy commonly used and to activate V9V2 T cells is the stimulation of tumor cells, monocytes, and dendritic cells (DC) with aminobisphosphonates (NBP) like pamidronate and zoledronate (ZA) (6). These drugs inhibit farnesylpyrophosphate synthase in the Mev pathway (7) leading to intracellular IPP accumulation and extracellular IPP release which is usually sensed by V9V2 T cells TCR and BTN3A1 (8). Wilhelm and colleagues (9) were the first to demonstrate that activation of V9V2 T cells with pamidronate and low-dose interleukin 2 (IL-2) could induce clinical responses in patients with B-cell lymphomas and multiple myeloma (MM). The ability of peripheral blood (PB) V9V2 T cells to proliferate after stimulation with pamidronate and IL-2 was a predictor of clinical response. A clinical trial of adoptively transferred activated V9V2 T cells in combination with ZA and IL-2 was well tolerated, but showed very limited clinical efficacy (9). Additional studies in solid tumors have also fallen short of clinical anticipations (10C13). Understanding why V9V2 T cells perform so poorly when intentionally recruited or to kill tumor cells is usually mandatory to really exploit their antitumor properties. One possible explanation is usually that activated V9V2 T cells do not reach the tumor site or, if reached, they are overwhelmed by the immune suppressive contexture operated by tumor cells and neighboring cells in the tumor microenvironment (TME). The TME is the protective niche which helps tumor cell to resist chemotherapy and escape immune surveillance (14). Although immune effector cells are often recruited in the TME by the tumor mutational load and the inflammatory milieu, their antitumor functions TD-106 are blunted by direct or indirect inhibitory signals generated by tumor cells and neighboring cells in the TME (15). V9V2 T cells are not exempted from this immune suppressive contexture operated soluble and cellular factors (16). Soluble factors include transforming growth factor-, prostaglandins, and kynurenins (17C19). Cellular factors include regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), bone marrow-derived stromal cells (BMSC), as well as others. The discovery that immune checkpoints (ICPs) and their ligands (ICP-L) are abundantly expressed by tumor cells, immune effector cells, and immune suppressive cells have helped to understand the mechanisms promoting the immune suppressive cross talk in the TME and provided new opportunities of interventions. In this review, we will discuss how the ICP/ICP-L circuitry undermines V9V2 T-cell function and how V9V2 T cells are very early and sensitive detectors of the TME immune suppressive contexture in MM patients. Lessons learned from V9V2 T cells in MM can be instrumental to improve V9V2 T-cell-based immunotherapy in cancer. The Immune Suppressive TME in Myeloma Multiple myeloma is usually a prototypic disease where malignant myeloma cells actively remodel the bone marrow (BM) microenvironment to establish a protective niche to support their growth, immune evasion, and drug resistance. MM is usually invariably preceded by a precursor asymptomatic stage of monoclonal gammopathy of undetermined significance (MGUS) with an estimated risk of progression to symptomatic disease ranging from less than 1% to more than 3% per year. This range depends on risk factors TD-106 traditionally ascribed to intrinsic features of myeloma cells. Genomic alterations determining clonal advantage are already detectable in MGUS indicating that the probability of progression is also dependent on extrinsic factors such as the composition of the surrounding TME (20). TME in MGUS and MM consists of a non-cellular component, the extracellular matrix, and of a heterogeneous cellular compartment that includes hematopoietic and non-hematopoietic cells. Both the noncellular and cellular components are edited by myeloma cells to TD-106 elude immune surveillance and insure their undisturbed survival and progressive growth (14, 15, 21). Immune escape in the BM of MGUS and MM patients is achieved by shifting the balance SCKL between immune effector and immune suppressor functions as in many other cancers. The immune suppressive mechanisms include.