In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and targeted therapies. However, not all cancer patients benefit from single or combination therapy with anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies. Thus, an increasing number of immune checkpoint proteins (ICPs) have been screened and their effectiveness evaluated in preclinical and clinical trials. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) constitute the second wave of immunotherapy targets that show great promise for use in the treatment of solid tumors and leukemia. To promote the research and clinical application of ICBs directed at these targets, we summarize their discovery, immunotherapy mechanism, preclinical efficiency, and clinical trial results in this review.

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.

T cells are fundamental effector cells against viruses and cancers that can be divided into different subsets based on their long-term immune protection and immediate immune response effects. The percentage and absolute number of these subsets change with ageing, which leads to a reduced immune response in older individuals. Stem cell memory T cells (T_SCM) represent a small population of memory T cells with enhanced proliferation and differentiation properties that are endowed with high potential for maintaining T cell homeostasis. However, whether these cells change with ageing and gender remains unknown. Here, we assayed the distribution of T_SCM and other T cell subsets in peripheral blood from 92 healthy subjects (44 females and 48 males) ranging from 3 to 88 years old by flow cytometry. We found that CD4+ and CD8+ T_SCM in the circulation have relatively stable frequencies, and the absolute number of CD8+ T_SCM decreased with age; however, the ratio of T_SCM to the CD4+ or CD8+ naïve population increased with age. Unlike the obvious changes in other T cell subsets with age and gender, the stable level of T_SCM in peripheral blood may support their capacity for sustaining long-term immunological memory, while their importance may increase together with ageing.

Acute promyelocytic leukemia (APL) is characterized by the reciprocal translocation t(15;17), which fuses PML with retinoic acid receptor alpha (RARα). Although PML-RARα is crucially important for pathogenesis and responsiveness to treatment, the molecular and cellular mechanisms by which PML-RARα exerts its oncogenic potential have not been fully elucidated. Recent reports have suggested that long non-coding RNAs (lncRNAs) contribute to the precise control of gene expression and are involved in human diseases. Little is known about the role of lncRNA in APL. We analyzed NEAT1 expression in APL samples and cell lines by real-time quantitative reverse transcription-PCR (qRT-PCR). The expression of PML-RARα was measured by Western blot. Cell differentiation was assessed by measuring the surface CD11b antigen expression by flow cytometry analysis. We found that nuclear enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in de novo APL samples compared with those of healthy donors. We further provide evidence that NEAT1 expression was repressed by PML-RARα. Furthermore, significant NEAT1 upregulation was observed during all-trans retinoic acid (ATRA)-induced NB4 cell differentiation. Finally, we demonstrate the importance of NEAT1 in myeloid differentiation. We show that reduction of NEAT1 by small interfering RNA (siRNA) blocks ATRA-induced differentiation. Our results indicate that reduced expression of the nuclear long noncoding RNA NEAT1 may play a role in the myeloid differentiation of APL cells.

To investigate the association between the T cell inhibitory receptor programmed death 1 (PD-1) and T cell exhaustion status in T cells from patients with de novo acute myeloid leukemia (AML) and AML in complete remission (CR). Surface expression of PD-1 and the exhaustion and immunosenescence markers CD244 and CD57 on CD3+, CD4+ and CD8+ T cells from peripheral blood samples from 20 newly diagnosed, untreated AML patients and 10 cases with AML in CR was analyzed by flow cytometry. Twenty-three healthy individuals served as control. A significantly higher percentage of PD-1+ cells were found for CD3+ T cells in the de novo AML group compared with healthy controls. In addition, an increased level of PD-1+CD8+ T cells, but not PD-1+CD4+, was found for CD3+ T cells in the de novo AML and AML-CR samples. A higher percentage of CD244+CD4+, CD244+CD8+, CD57+CD4+ and CD57+CD8+ T cells was found in CD3+ T cells in samples from those with de novo AML compared with those from healthy controls. Strong increased PD-1+CD244+ and PD-1+CD57+ co-expression was found for CD4+ and CD8+ T cells in the de novo AML group compared with healthy controls. We characterized the major T cell defects, including co-expression of PD-1 and CD244, CD57-exhausted T cells in patients with de novo AML, and found a particular influence on CD8+ T cells, suggesting a poor anti-leukemia immune response in these patients.

Characterization of functional T cell clusters is key to developing strategies for immunotherapy and predicting clinical responses in leukemia. 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). Unbiased bioinformatics analysis enabled the authors to identify 13 T cell clusters in the patients based on their molecular properties. 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. Two exhausted T cell populations, characterized by up‐regulation of TIGIT, PDCD1, HLADRA, LAG3, and CTLA4 are specifically discovered in B‐ALL patients. 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. 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. Together, these data provide for the first‐time valuable insights for understanding exhausted T cell populations in leukemia.