Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 in T cells from patients with non‐Hodgkin lymphoma

Abstract

Aim: To characterize immune suppression in lymphoma, thymocyte selectionassociated high mobility group box protein (TOX) expression and co-expression with programmed cell death receptor-1 (PD-1), T cell immunoglobulin mucin-domaincontaining-3 (Tim-3), and CD244 in CD3+, CD4+, CD8+, and regulatory T (Treg) cells from patients with lymphomas were analyzed.Methods: TOX expression and co-expression with PD-1, Tim-3, and CD244 in CD3+, CD4+, Treg, and CD8+ T cells were analyzed by multi-color fluorescent flow cytometry using peripheral blood (PB) from 13 newly diagnosed, untreated lymphoma patients, and 11 healthy individuals.

Increased TOX expression concurrent with PD‐1, Tim‐3, and CD244 expression in T cells from patients with acute myeloid leukemia

“…In this study, we examined the characteristics of TOX in T cell subsets and found a significantly increased percentage of TOX+ CD3+, CD4+, and CD8+ T cells in PB from AML patients. This result is consistent with findings of upregulation of TOX in solid tumors and lymphomas (Huang et al, 2021; Kim et al, 2020; Liang, Zhao, et al, 2021; Wang et al, 2019; Yang et al, 2021). TOX+CD244+, TOX+PD‐1+, and TOX+Tim‐3+ double‐positive T cells were evidently increased in the CD3+, CD4+, and CD8+ T cell populations, suggesting that TOX may play a vital role as a transcription factor in the formation of exhaustive T cells.…”

“…Cell surface staining analysis for PD‐1, Tim‐3, CD244, CD25, CD3, CD4, CD8, and CD45 and intranuclear staining analysis for TOX and FoxP3 were performed with a BD FACS Canto flow cytometer (BD Biosciences, San Jose, USA) and Flowjo software (Flowjo LLC, USA) as previously described (Huang et al, 2021; Kasakovski et al, 2021). The antibodies used for this study were purchased from BD Biosciences (San Jose, USA) and eBioscience (San Diego, USA).…”

“…Our recent study also demonstrated that TOX is highly co‐expressed with PD‐1, Tim‐3, and CD244 in CD3+ T cells and particularly in CD8+ T cells in patients with B cell non‐Hodgkin's lymphoma (B‐NHL). Furthermore, the proportions of both TOX+ and TOX+PD‐1+ regulatory T (Treg) cells are also significantly increased in B‐NHL patients, suggesting that TOX contributes to promoting T cell exhaustion (Huang et al, 2021). Thus, TOX may be a potential target for immunotherapy in hematological malignancies (Liang, Huang, et al, 2021).…”

Higher TOX Genes Expression Is Associated With Poor Overall Survival for Patients With Acute Myeloid Leukemia

“…It is possible that the association between TOX and PD-1 or CTLA-4 co-expression only occurs in T cells (21) and not PBMCs, which include a high percentage of AML cells. We found that TOX genes are also expressed in AML cell lines and primary AML cells (data not shown), which suggests that there are different patterns of expression for TOX genes in T cells and AML cells, which may play a different role.…”

“…In our previous study, we found higher TOX expression concurrent with PD-1, Tim-3, or CD244 in T cells from patients with B cell non-Hodgkin's lymphoma (B-NHL), which suggested that TOX may be involved in inducing CD8+ T cell exhaustion by co-regulation with immune checkpoint proteins (21).…”