Characterization of t cell exhaustion in multiple myeloma

Abstract

Immune checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 monotherapy has not shown clinical efficacy in multiple myeloma (MM). I obtained bone marrow (BM) mononuclear cells from 52 newly diagnosed MM patients and examined the ex-pression profile of checkpoint receptors on BM $CD8^+$ T cells and their functional restoration by anti-PD-1. I confirmed upregulation of PD-1 and PD-L1 expression in $CD8^+$ T cells and myeloma cells, respectively, from the BM of MM patients. PD-1-expressing CD8+ T cells from the BM of MM patients co-expressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype represented by $Eomes^{hi}$T-$bet^{lo}$. These results were also observed in BM $CD8^+$ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM $CD8^+$ T cells from MM patients exhibited reduced proliferation and cytokine production upon the stimulation of T-cell receptor signals compared to those from patients with other asymptomatic plasma-cell neoplasms and other B-cell lymphomas. However, anti-PD-1 did not increase the proliferation of BM $CD8^+$ T cells from MM patients, but it increased the proliferation of those cells from other $\beta$-cell lympho-mas, indicating that the T-cell exhaustion in MM is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation and cytokine production of BM $CD8^+$ T cells from MM patients in the presence of transforming growth factor-$\beta$ (TGF-$\beta$) inhibitors, such as anti-TGF-$\beta$1 blocking antibodies and TGF-$\beta$ receptor-1 inhibitor, suggesting that the combined blockade of PD-1 and TGF-$\beta$ may be useful for the treatment of MM.