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  • We stimulated HNEpC cells with

    2024-05-11

    We stimulated HNEpC cells with LPS found that the secretion of inflammatory cytokines and the expression of AHR was increased significantly, and miR124 was reduced. It has been found that LPS as a foreign substance can bind to the TLR family of proteins to activate intracellular AHR signaling [[19], [20], [21]]. AHR has a strong anti-inflammatory effect, for example, it can promote the Trl cells that express IL-10, affect the secretion of IL-17 and IL-22 by TH17 cells [22], and induce the tolerance phenotype of dendritic cells [23,24]. Our results show that knockdown of AHR can rescue the secretion of inflammatory cytokines caused by LPS, and AHR may play an irreplaceable role in the process of LPS-induced cellular inflammation (Fig. 4). MiR124 may participate in the regulation of the body's inflammatory response through the LPS-TLR-AHR signaling pathway, which requires our further study. The use of targeted drugs for the treatment of chronic rhinitis-sinusitis is still an important challenge for the treatment of patients with chronic rhinitis. Our results suggest that miR124 may be used as a new biomarker for predicting chronic nasosinusitis-targeted drugs, and it is important for the study and treatment of chronic rhinitis and sinusitis. However, we acknowledge that we have not studied the role of miR124 in primary cultured nasal mucosa tissue as a limitation of this study.
    Conflict of interest
    Acknowledgments and Funding This work was supported by grants of the Key research and development plan of Shandong Province (No.2016GSF201077) and grants from the National Natural Science Foundation of China (Grant-awarded Numbers 81770979, and 81672093, 81670909).
    Cancer Immunotherapy Recent success in cancer immunotherapies, illustrated by immune checkpoint inhibitors, including US FDA-approved biologic drugs targeting the programmed death receptor/ligand 1 (PD-1/PD-L1), cytotoxic T lymphocyte associated protein 4 (CTLA-4) BMS354825 [1], and adoptive cell transfer therapies [2], has brought renewed hopes that cancer, after all, can be managed as a curable disease instead of a death sentence. Traditionally, anticancer modalities (irradiation, chemotherapy, and targeted therapy) exert their therapeutic effects by directly killing proliferating cancer cells. Their usefulness has been limited by toxicity and by rapid development of resistance. Cancer immunotherapies aim to harness the immune system to eradicate cancer cells and control tumor growth. The approval of immune checkpoint inhibitors illustrates the success in fighting cancer by activating T cell-mediated adaptive immunity. Two signals are required for a full T cell response to pathogens. First, native T cells are stimulated by antigen-presenting cells (APCs) that present pathogen peptide epitopes to the T cell receptor (TCR) via the engagement of the major histocompatibility complex (MHC). Effective presentation of cancer-derived neoantigens by APCs is a prerequisite for the immune system to recognize cancer as a danger and to initiate an immune response. A second costimulating signal is required for the expansion of primed T cells. Cancer cells can seize control of the costimulating machinery to inhibit the expansion and function of effector T cells through upregulation of immune checkpoint molecules including CTLA-4 and PD-1. CTLA-4 and PD-1 are expressed in T cells and negatively regulate their effector functions. Checkpoint inhibitors prevent engagement of CTLA-4 and PD-1 with their corresponding ligands, and enable the body to mount potent antitumor immunity by overcoming immune-evasion mechanisms mounted by cancer cells. In many cases checkpoint inhibitors have achieved unprecedented durable responses in advanced cancer patients. Cancer immunotherapies expand our armaments beyond cytotoxic and targeted therapies to win more battles against cancer [3]. However, a significant majority of cancer patients do not respond to existing immune checkpoint inhibitors, and the emergence of treatment-induced resistance is common in patients who initially responded [4]. The responders seem to carry an inflammatory T cell signature in their tumor microenvironment (TME; see Glossary): functional neoantigen presentation by dendritic cells (DCs) and infiltration and proliferation of tumor-specific cytotoxic T lymphocytes (CTLs) [5]. Therefore, novel strategies capable of transforming the immunosuppressive TME of non-T cell inflammatory (dubbed ‘cold’) tumors to inflammatory tumors may portend a new paradigm in cancer immunotherapy. Under the spotlight are the tryptophan catabolic enzymes IDO1/TDO2 and their product KYN. Recent research has revealed that KYN is a key signaling molecule that can transduce the immunosuppressive effects of IDO1 and TDO2. Furthermore, IDO1 has been shown to participate in mechanisms of resistance to checkpoint inhibitors, making the combination of an IDO1 inhibitor with a checkpoint inhibitor a promising strategy to expand patient populations for immunotherapies. We provide here updates on recent advances in the development of novel anticancer immunotherapies targeting both the upstream and downstream effector molecules of KYN.