Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy

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

“…35,36 To further address this phenomenon, the expression and function of the TCR signaling pathway, activation and inhibitory receptors in T cells were analyzed. For example, lower TCR expression reduced T cell activation and cytotoxicity, 8,35 and up-regulation of PD-1 and Tim-3 significantly reduced T cell function and promoted T cell exhaustion. 11,32,37 In this study, we further characterized the distribution of PD-1+ T cells in TCR V subfamily CD4+ and CD8+ T cells, high trends of PD-1 expression in all TCR V subfamily T cells in AML, and a significantly increased percentage of PD-1+ CD4+ and CD8+ T cells in most of the TCR V subfamilies indicated that a lower number of V T cells with a higher percentage PD-1+ T cells is the reason for the lowered immune response in AML.…”

“…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.…”

Will deeper characterization of the landscape of immune checkpoint molecules in acute myeloid leukemia bone marrow lead to improved therapeutic targeting?

“…This was done despite the lack of comprehensive analyses of PD‐L1 expression and T‐cell infiltration in the human myeloid leukemia bone marrow microenvironment. Recently, studies characterizing T‐cell dysfunction and the cells’ reversibility with intensive chemotherapy in patients with AML have been published, but a detailed understanding of the dynamic and serial changes in the immune checkpoint molecules is lacking . In this issue of Cancer , Williams et al, in an exhaustive manner, explored the bone marrow microenvironment including, but not limited to, PD‐L1 expression and the quantity of infiltrated T cells .…”

“…Recently, studies characterizing T-cell dysfunction and the cells' reversibility with intensive chemotherapy in patients with AML have been published, but a detailed understanding of the dynamic and serial changes in the immune checkpoint molecules is lacking. 4,5 In this issue of Cancer , Williams et al, in an exhaustive manner, explored the bone marrow microenvironment including, but not limited to, PD-L1 expression and the quantity of infiltrated T cells. 6 They assessed the T-cell quantity in healthy versus AML bone marrow and demonstrated the expression pattern of a set of targetable coinhibitory and costimulatory receptors on T cells, and their respective ligands on the AML blasts, using multicolor flow cytometry.…”