![]() ] Exhausted T cells could be defined by sustained expression of inhibitory receptors ( CTLA‐4, PD‐1, TIGIT, LAG3, TIM3). The efficacy of many checkpoint inhibitors largely depends on their ability to reduce CD8 + cytotoxic T cells in the microenvironment, whose cytotoxic ability may be rendered inactive by reaching a T cell dysfunction state called exhaustion. Because the immune microenvironment is highly complex, evaluation of clinical outcome requires deep understanding of the T cells underlying the leukemia. ] Whether the properties of the host immune system affect disease risk or outcome in leukemia is unknown. Therefore, deepening the understanding of inhibition states and the functional heterogeneity of T cells in patients will be paramount to revealing new therapeutic targets.Ĭurrently, prognostic factors for leukemias depend on their risk stratification, including the genomic features of leukemia cells and clinical characteristics, for example, age, the count of white blood cell (WBC) at diagnosis, and response to chemotherapy. ] For instance, the efficacies of CAR‐T cell therapy are not uniform among patients and closely related to the activity of derived T cells. ] Furthermore, it is increasingly appreciated that the immune microenvironment governs the strength of the anticancer response following immune therapies. ] T cells with chimeric antigen receptors (CARs) have led to impressive responses and encouraging outcomes in patients with hematological malignancies. Over the past decade, immune‐based approaches such as monoclonal antibody therapy and checkpoint inhibitor therapy have emerged. Therefore, new strategies using fewer toxic elements are urgently needed. ] Current chemotherapies aim at killing abnormal leukemia cells while inevitably damaging normal cells and carrying significant risk of long‐term toxicities. ] Although most patients initially respond to chemotherapy, ≈60% relapse, and only 30% survive within 5 years thus, overall anti‐tumor responses remain limited. Together, these data provide for the first‐time valuable insights for understanding exhausted T cell populations in leukemia.ī cell‐acute lymphoblastic leukemia (B‐ALL) is a clonal hematopoietic disease characterized by the abnormal proliferation and accumulation of B‐lymphoid progenitor cells. Coupled with single‐cell T cell receptor repertoire profiling, diverse originations of the exhausted T cells in B‐ALL are suggested, and clonally expanded exhausted T cells are likely to originate from CD8 + effector memory/terminal effector cells. Of note, these exhausted T cells possess remarkable heterogeneity, and ten sub‐clusters are further identified, which are characterized by different cell cycle phases, naïve states, and GNLY (coding granulysin) expression. Two exhausted T cell populations, characterized by up‐regulation of TIGIT, PDCD1, HLADRA, LAG3, and CTLA4 are specifically discovered in B‐ALL patients. All 11 major T cell subsets in healthy individuals are found in the patients with B‐ALL, with the counterparts in the patients universally showing more activated characteristics. Unbiased bioinformatics analysis enabled the authors to identify 13 T cell clusters in the patients based on their molecular properties. Here, single‐cell RNA sequencing is performed with T cells sorted from the peripheral blood of healthy individuals and patients with B cell‐acute lymphoblastic leukemia (B‐ALL). ![]() Characterization of functional T cell clusters is key to developing strategies for immunotherapy and predicting clinical responses in leukemia. ![]()
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