Increased exhausted CD8+ T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma

Abstract

Aim: The immunosuppressive microenvironment plays a crucial role in T-cell immunodeficiency in multiple myeloma (MM). Overexpression of T-cell immunosuppressive receptors, including programmed death-1 (PD-1) and T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3), may be related to tumor immunosuppression and poor prognosis, and the malignant bone marrow (BM) microenvironment may contribute to such immunosuppression. The purpose of this study was to analyze the distribution of PD-1⁺ and/or Tim-3⁺ T cells in different T-cell subset in patients with MM.

Methods: The expression of PD-1 and Tim-3 with exhausted (CD244⁺ and CD57⁺ ) CD3⁺ , CD4⁺ and CD8⁺ T cells between BM and peripheral blood (PB) from 10 patients with untreated MM was detected by multicolor flow cytometry assay.

Results: A significant increase in both PD-1⁺ CD57⁺ and Tim-3⁺ CD57⁺ CD3⁺ T cells and PD-1⁺ Tim-3⁺ CD3⁺ T cells was detected in PB from patients with MM compared with 10 healthy individuals (HIs), and the alteration was mostly in the CD8⁺ T-cell subset. Significant higher percentage of PD-1⁺ CD3⁺ T cells was found in BM compared with PB from patients with MM. The level of PD-1⁺ Tim-3⁺ CD3⁺ , CD4⁺ , and CD8⁺ T cells was high in BM group compared with PB. Moreover, PD-1⁺ CD244⁺ or PD-1⁺ CD57⁺ CD3⁺ T cells, particularly PD-1⁺ CD244⁺ and PD-1⁺ CD57⁺ CD8⁺ T cells were significantly higher in BM than in PB. In addition, limited dynamic detection data from three MM cases who achieved complete remission after treatment showed that the numbers of either PD-1⁺ or PD-1⁺ Tim-3⁺ T cells in different T-cell subsets were decreased in both BM and PB.

Conclusion: We characterized the distribution of PD-1 and TIM-3 concurrent with exhausted CD3⁺ , CD4⁺ and CD8⁺ T cells between BM and PB from patients with MM. Higher numbers of PD-1⁺ CD244⁺ or PD-1⁺ CD57⁺ CD3⁺ T cells in BM from patients with MM may contribute to mediate the BM immunosuppressive microenvironment. Although heterogeneous alterations in Tim-3⁺ T cells may represent a complex immunosuppressive pattern in MM. Overall, higher levels of PD-1⁺ CD244⁺ or PD-1/Tim-3⁺ CD57⁺ CD8⁺ T cells may be a major reason for lower T-cell activation and T-cell immunodeficiency in MM.

Keywords: PD-1; T-cell exhaustion; T-cell subset; Tim-3; multiple myeloma.