Anergic bone marrow V?9V?2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma.

ABSTRACT: V?9V?2 T cells have a natural inclination to recognize malignant B cells in vitro via receptors for stress-induced self-ligands and TCR-dependent recognition of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. This inclination is continuously challenged in vivo by the immune suppression operated by tumor cells. Multiple myeloma (MM) is a prototypic B-cell malignancy in which myeloma cells subvert the local microenvironment to reshape antitumor immune responses. In this study, we have investigated the immune competence of bone marrow (BM) V?9V?2 T cells in a large series of MM patients. We have found that the BM microenvironment significantly hampers the pAg-reactivity of BM V?9V?2 T cells, which become largely PD-1⁺ and are surrounded by PD-L1⁺ myeloma cells and increased numbers of PD-L1⁺ myeloid-derived suppressor cells (MDSC). V?9V?2 T-cell dysfunction is an early event that can be already detected in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission. Anti-PD-1 treatment increases the cytotoxic potential of V?9V?2 T cells by almost 5-fold after pAg stimulation, and appears to be a promising strategy for effective immune interventions in MM.

SUBMITTER: Castella B 

PROVIDER: S-EPMC4589055 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature