Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Abstract

Background: 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 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. Methods: PB 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. Results: The 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. Conclusions: Upregulation 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.

Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia

“…Although TIGIT expression had no effects on CD8 + T cells, it was associated with impaired cytokine production ability of CD4 + T cells in patients with CLL. Despite previous reports on the important role of TIM-3 and Gal-9 interactions in T cell exhaustion in hematological and non-hematological cancers, 60 61 we observed a very low expression level of these co-inhibitory receptor/ligand in T cells of patients with CLL.…”

Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

“…Periphery blood (PB) samples of AML patients showed us the immune dysfunction of lymphocytes based on the analysis of flow cytometry and immune-related risk of factors, indicated that the immune signatures corrected clinical outcomes [ 36 ]. The immune status of BM microenvironment are more sensitive to reflect immune response for clearing AML blast cells compared to PB [ 37 ]. So dissecting the immune landscape of AML is important for predicting the immune status and screening suitable immunoregulatory drugs.…”

Characteristic of TIGIT and DNAM-1 Expression on Foxp3+ γδ T Cells in AML Patients

“…It is well known that T cells with the exhausted and suppressive phenotype may have reduced activation and be related to poor prognosis for AML patients [21,22]. Elucidation of the role of TIGIT on γδ Tregs in this context may assist in understanding the dysfunctional immunobiology of γδ cells in AML patients of different clinical statuses.…”