Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia

Abstract

Stem cell memory T (TSCM) and central memory T (TCM) cells can rapidly differentiate into effector memory (TEM) and terminal effector (TEF) T cells, and have the most potential for immunotherapy. In this study, we found that the frequency of TSCM and TCM cells in the CD8+ population dramatically decreased together with increases in TEM and TEF cells, particularly in younger patients with acute myeloid leukemia (AML) (< 60 years). These alterations persisted in patients who achieved complete remission after chemotherapy. The decrease in TSCM and TCM together with the increase in differentiated TEM and TEF subsets in CD8+ T cells may explain the reduced T cell response and subdued anti-leukemia capacity in AML patients.

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

“…With the recent development of targeted and immunotherapy, a number of ongoing studies aim to produce novel AML therapies, including conventional cytotoxic chemotherapies, genetic and epigenetic targeted therapies, and immunotherapies [3][4][5][6]. The T cell immune status of patients is an important factor related to the prognosis of leukemia [7][8][9][10][11]. Significantly, improvement in the clinical outcome of hematological malignancies was demonstrated by using immunotherapies such as CAR-T cell transfusion [12][13][14][15].…”

“…Although considerable progress has been made in this field, the achievements of ideal effects in solid tumors and acute lymphoblastic leukemia (ALL) have not been realized for AML. Thus, further analysis of the T cell immune dysfunction that exists in AML patients and their causes remain necessary [8]. It is well known that cancerassociated immune suppression can significantly reduce T cell-mediated anticancer immunity.…”

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

“…[11][12][13][14] However, unlike in solid tumors, the clinical efficacy of immune checkpoint inhibition, particularly PD-1 inhibitor monotherapy, appears to be limited in AML, MDS, and multiple myeloma (MM), [15][16][17][18] which may be due to the complexity of the leukemic bone marrow (BM) microenvironment in which persistent stimulation of leukemia cell-derived antigen results in more complex T-cell exhaustion and dysfunction. [19][20][21] In this case, more than one immune inhibitory receptor may contribute to T-cell dysfunction. The heterogeneity of exhausted T cells may be a reason for the lower effects of PD-1 inhibitors.…”

A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

“…However, unlike B‐cell leukemia and lymphoma, the application of immunotherapy for acute myeloid leukemia (AML) has been limited due to limited understanding of global T cell immune dysfunction in AML . Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML at diagnosis, and impairment of T cell function might be mediated by up‐regulating immune checkpoint receptors, such as programmed death‐1 (PD‐1), lymphocyte‐activation gene 3, T‐cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) . For example, CD8+ T cell dysfunction in AML was in part reversible upon PD‐1 blockade in vitro, and PD‐1 blockade could enhance CD33‐CD3 BiTE antibody construct‐mediated cytotoxicity in AML .…”

“…6,7 Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML Abbreviations: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CAR, chimeric antigen receptor; CR, complete remission; NCR, non-complete remission; PD-1, programmed death-1,; Tim-3, T cell immunoglobulin and mucin-domain containing-3. at diagnosis, 8,9 and impairment of T cell function might be mediated by up-regulating immune checkpoint receptors, such as programmed death-1 (PD-1), lymphocyte-activation gene 3, T-cell immunoglobulin and mucin-domain containing-3 (Tim-3). [10][11][12][13] For example, CD8+ T cell dysfunction in AML was in part reversible upon PD-1 blockade in vitro, 7 and PD-1 blockade could enhance CD33-CD3 BiTE antibody construct-mediated cytotoxicity in AML.…”