Regulation of T cell differentiation by the AP-1 transcription factor JunB. Katagiri Takaharu,Kameda Hideto,Nakano Hiroyasu,Yamazaki Soh Immunological medicine JunB, a component of the activator protein-1 (AP-1) transcription factor, is known to exhibit an important role in bone formation and bone marrow cell proliferation. During T helper type 2 (Th2) cell differentiation, JunB contributes to the regulation of interleukin (IL)-4 expression, and AP-1 and nuclear factor of activated T cell (NFAT) constitute a heteromer and contribute to IL-2 production. However, the role of JunB in other T cells has not been investigated. In 2017, it was revealed that JunB, in collaboration with basic leucine zipper ATF-like transcription factor (BATF), regulates the expression of Th17-related genes. Furthermore, JunB was found to play an important role in regulatory T (Treg) cell differentiation, contributing to CD25 expression and IL-2 production. IL-2 is a T cell activator and has been shown as a necessary factor for Treg proliferation. Here, we review the role of JunB in T cells based on basic research data and discuss the potential for its clinical applications. 10.1080/25785826.2021.1872838

Emerging Therapies for Hepatocellular Carcinoma (HCC). Cancers Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (), catenin beta 1 () and tumor protein p53 () genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment. 10.3390/cancers14112798

Coexpression of in multiple-chain DAP-CAR-engineered T-cells for solid tumor therapy. Immunotherapy This work was designed to explore whether c-Jun overexpression could improve the persistence and antitumor efficacy of DAP chimeric antigen receptor T-cell (CAR-T) cells. The and antitumor effects of mesothelin (MSLN) targeting DAP-CAR-T cells were verified by ELISA, real-time cell analysis and in a xenograft model. overexpression did not affect DAP-CAR-T cell expansion while slightly increasing IL-2 secretion. Moreover, c-Jun did not improve the antitumor efficacy of DAP-CAR-T cells  or , but reduced LAG3 expression and increased the ratio of Tcm and Tn/Tscm cells . The findings indicate that coexpression with c-Jun in DAP-CAR-T cells slightly improves T-cell exhaustion and central memory phenotype maintenance, which may be useful for DAP-CAR-T cell therapy in solid tumors. 10.2217/imt-2022-0171

c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents. 10.1038/s41586-019-1805-z

Improving the ability of CAR-T cells to hit solid tumors: Challenges and strategies. Zhang Zheng-Zheng,Wang Tian,Wang Xiao-Feng,Zhang Yu-Qing,Song Shu-Xia,Ma Cui-Qing Pharmacological research Chimeric antigen receptor T cell (CAR-T) therapy is a late-model of immune cell therapy that has been shown to be effective in refractory/recurrent B-cell leukemia and lymphoma. Compared with the traditional anti-tumor methods, CAR-T cell therapy has the advantages of higher specificity, stronger lethality and longer-lasting efficacy. Although CAR-T cells have made significant progress in the treatment of hematologic malignancies, diverse difficulties remain in the treatment of solid tumors, including immune escape due to tumor antigen heterogeneity, preventing entry or limiting the persistence of CAR-T cells by physical or cytokine barriers and along with other immunosuppressive molecule and cells in the tumor microenvironment (TME). Otherwise, the intracellular signaling of CAR also impact on CAR-T cells persistence. Appropriate modification of intracellular costimulatory molecular signal in the structure of CAR or coexpression of CAR and cytokines can provide a way to enhance CAR-T cells activity. Additionally, CAR-T cells dysfunction due to T cell exhaustion is associated with multi-factors, especially transcription factors, such as c-Jun, NR4A. Engineering CAR-T cells to coexpress or knockout transcription factors in favor of T memory CAR-T cells differentiation was proved to prolonged the survival of CAR-T cells. Finally, combination of CAR-T cells with oncolytic viruses, nanoparticles or immune checkpoint inhibitors provides an effective measure to improve CAR-T cells function. Here, we discuss all of these advances and challenges and review promising strategies for treating solid tumors. In particular, we also highlight that CAR-T cells have enormous potential to be used in combination with other immunotherapies. 10.1016/j.phrs.2021.106036