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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Bone marrow (BM) V\u03b39V\u03b42 T cells are intrinsically predisposed to\u00a0sense the immune fitness of the tumor microenvironment (TME) in multiple\u00a0myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this work, we have used BM V\u03b39V\u03b42 T cells to interrogate the role of the immune checkpoint\/immune checkpoint-ligand (ICP\/ICP-L) network in the immune suppressive TME of MM patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PD-1+ BM MM V\u03b39V\u03b42 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM V\u03b39V\u03b42 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM V\u03b39V\u03b42 T cells up-regulate TIM-3 after stimulation with ZA in combination with \u03b1PD-1, whereas PD-1 is not up-regulated after ZA stimulation with \u03b1TIM-3, indicating a hierarchical regulation of inducible ICP expression. Dual \u03b1PD-1\/\u03b1TIM-3 blockade improves the immune functions of BM V\u03b39V\u03b42 T cells in MM at diagnosis (MM-dia), whereas single PD-1 blockade is sufficient to rescue BM V\u03b39V\u03b42 T cells in MM in remission (MM-rem). By contrast, ZA stimulation induces LAG-3 up-regulation in BM V\u03b39V\u03b42 T cells from MM in relapse (MM-rel) and dual PD-1\/LAG-3 blockade is the most effective combination in this setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These data indicate that: 1) inappropriate immune interventions can exacerbate V\u03b39V\u03b42 T-cell dysfunction 2) ICP blockade should be tailored to the disease status to get the most of its beneficial effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2022.1073227","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T03:27:35Z","timestamp":1671506855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Immune dysfunctions affecting bone marrow V\u03b39V\u03b42 T cells in multiple myeloma: Role of immune 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