Abstract
BackgroundAltered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome.MethodsPB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry.ResultsThe proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy.ConclusionsUpregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.
Highlights
Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression
We found significantly increased programmed death-1 (PD-1) + CD3+ and PD-1 + CD8+ T cells in BM in comparison with peripheral blood (PB); there was no statistically significant difference in the percentage of PD-1 + CD4+ T cells between the BM and PB (Fig. 1b)
We examined the co-expression of PD-1 or T cell immunoglobulin mucin-3 (Tim-3) with CD244 and CD57, and higher percentages of PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in the BM group
Summary
Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. It has been demonstrated that T cell immune inhibitory receptors, known as immune checkpoint receptors, such as program death-1 (PD-1), T cell immunoglobulin mucin 3 (Tim-3), cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) and T cell lymphocyte activation gene-3 (LAG-3) have increased expression in T cells in patients with newly diagnosed and relapsed AML and murine AML models [19,20,21,22]. Tim-3 as a trafficker for the secretion of Gal-9 may contribute to AML development [25, 26] This finding may indicate one of the reasons for the anti-cancer T cell activity impairment in AML. PD-1 blockade alone or in combination with blockade of other immune checkpoint proteins can improve the anti-leukemia CD8+ T cell function in murine AML models [2, 18, 24]
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