T cell senescence and CAR-T cell exhaustion in hematological malignancies

Abstract

T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies.

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

“…Immunotherapy‐like immune checkpoint blockade, chimeric antigen receptor (CAR)‐ and TCR‐modified T cells have entered main street for both solid tumor and hematologic malignancies . 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 .…”

“…Immunotherapy-like immune checkpoint blockade, chimeric antigen receptor (CAR)-and TCR-modified T cells have entered main street for both solid tumor and hematologic malignancies. [1][2][3][4][5] 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. 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.…”

CD8+ iT cell, a budding star for cancer immunotherapy

“…Chimeric antigen receptor T cells (CAR-T) and T cell receptor T cells (TCR-T) are promising forms of immunotherapy against leukemia and solid tumors (Im and Pavletic 2017;Lin et al 2017;Kasakovski et al 2018). However, conventional CAR-T and TCR-T cell products are mainly derived from the autologous peripheral blood of patients, whose T cells occasionally showed functional exhaustion and senescence and reduced response to activation, which were correlated with patient's age, tumor burden, or microenvironment (Crespo et al 2013;Vicente et al 2016;Lin et al 2017;Kasakovski et al 2018).…”

“…However, conventional CAR-T and TCR-T cell products are mainly derived from the autologous peripheral blood of patients, whose T cells occasionally showed functional exhaustion and senescence and reduced response to activation, which were correlated with patient's age, tumor burden, or microenvironment (Crespo et al 2013;Vicente et al 2016;Lin et al 2017;Kasakovski et al 2018). In order to overcome difficulties faced in CAR-T and TCR-T production, which were caused by the limited quantity, function impairment, and the terminally differentiated state of autologous T cells from patients, an alternative approach has been attempted in the T cell regenerative filed by generating tumor-targeted T cells from induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells, such as peripheral blood cells and even T cells (Loh et al 2010;Themeli et al 2013;Vizcardo et al 2013).…”