Dual identity of IFN-γis wonderful in immunity

01. IFN-γ signaling pathway

Interferon-γ (IFN-γ) is a soluble dimer cytokine, which belongs to type II interferon, and is mainly secreted by natural killer cells (NK) and natural killer T cells (NKT) cells. From a biological point of view, IFN-γ is a pleiotropic cytokine with multiple functions of anti-virus, anti-tumor and immune regulation. Compared with other members of the interferon family, IFN-γ has outstanding performance in the field of immune regulation. It can activate other immune cells and promote immune responses. It is called immune interferon.

IFN-γ performs biological functions through the IFNGR1/2 receptor- mediated signal transduction pathway. Receptor activation of IFN-γ causes JAK1 and JAK2 to phosphorylate STAT1, phosphorylated STAT1 forms homodimers, translocates into the nucleus, and activates critical IFN-γ responses by binding to the GAS motif within its promoter Gene.

02. IFN-γ immune function

IFN-γ is a key cytokine related to anti-tumor immunity. It protects the human body by exerting cytostatic function, promoting cancer cell apoptosis and immune stimulation; it also plays an important role in vitro. The classic cytokine induced by Schmidt established in 1991 In the Cytokine-Induced Killer (CIK) culture program, IFN-γ is an inducing factor that must be added. Thanks to its up- regulation of the expression of MHC molecules and a series of transcriptional regulatory molecules, CIK cells can function better. In a study related to lung cancer, the experimental team performed immunohistochemical processing on tumor tissues of different patients and found that patients who expressed IFN-γ and PD-L1 at the same time had a more favorable prognosis than patients who expressed IFN-γ alone, while PD-L1 is a well-established inhibitor of antitumor immune function, suggesting that PD-L1 may serve as a biomarker of tumor sensitivity to IFN-γ inhibition, which triggers the three PI3K-AKTs in a JAK2-dependent manner activation pathway [1].

03. Dual identity of IFN-γ

With the in-depth study of the tumor microenvironment in the scientific community, the other side of IFN-γ has also surfaced. Professor Zaidi's research group proposes that IFN-γ protects cells from damage caused by tissue remodeling and repair, and that the same mechanism works in cells with cancer-causing mutations. In fact, a 1987 report suggested that tumor cells could utilize IFN-γ as an inducer of anti-inflammatory and pro-neoplastic effects [2]. IFN-γ seems to be a "double-faced agent". While calling on other immune cells to strangle cancer cells, it also opens a back door for cancer cells to escape from the immune system. However, the study of the tumor microenvironment is still in the development stage, and it may be a bit hasty to make a conclusion on the role of IFN-γ at this moment. The signal induced by IFN-γ is always combined with the signal transduction mediated by other factors. This dual role is both a challenge and a great opportunity, which broadens the research ideas of scientific researchers.

04. Research on application and development of IFN-γ

The role of IFN-γ in anti-tumor immunity has attracted more and more attention from the research and development of pharmaceutical companies . Researchers at home and abroad have carried out a number of clinical trials using IFN-γ as a therapeutic target. Axceso Biopharma is developing a novel kinase inhibitor, AX-0085, which can inhibit IFN-γ-induced PD-L1 expression in lung adenocarcinoma cells, effectively blocking IFN-γ-triggered JAK2/STAT1 signaling , and prevented the nuclear localization of STAT1.

The transcriptome data also shows that AX-0085 largely reverses the expression pattern induced by IFN-γ[3], and many studies have also shown that in the treatment of immune checkpoints, the production of IFN-γ by tumor suppressor cells and IFN-γ signaling in cancer cells can be used to evaluate the therapeutic effect of anti-cancer treatment [4].

The world is shrouded in the shadow of the new crown, and people's attention to various infectious diseases is also at the highest point. We urgently need to discover efficient targets and develop corresponding drugs to combat the increasingly severe potential epidemic. IFN-γ is the central effector of cell-mediated immunity, which can coordinate a variety of antimicrobial functions [5]. For example, IFN-γ can induce autophagy and promote the fusion of phagosomes to activate antibacterial activity against pathogens that invade the host.

A recent article published in the journal J Microbiol Immunol Infect stated that anti-IFN-γ therapy can significantly alleviate pulmonary hemorrhage and inflammatory cell infiltration in mouse models due to acute lung injury. The increase in the number of cytokines and chemokines may lead to the overproduction of neutrophils and monocytes to aggravate the inflammatory response, and the secretion of these factors is affected by IFN-γ, which explains the neutralization of IFN-γ. The reason for the obvious improvement of the inflammatory response in the model mice. Based on the results of the study, researchers predict that monoclonal antibodies against IFN-γ can be used as potential therapeutic drugs for future influenza pandemics [6].

05. Summary

IFN-γ plays an important role in the entire immune system, and its research and application seem to be at a crossroads. This seems to be a limitation, but breakthrough research often turns limitations into creativity and exerts Amazing energy. It is believed that with the deepening of research, IFN-γ can provide ideas for more immunotherapy.

References:

【1】 Gao Y, Yang J, Cai Y, Fu S, Zhang N, Fu X, Li L. IFN-γ-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling. Int J Cancer. 2018 Aug 15;143(4):931-943.

【2】Castro F, Cardoso AP, Gon?alves RM, Serre K, Oliveira MJ. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front Immunol. 2018 May 4;9:847 .

【3】 Kim J, Jang H, Lee GJ, Hur Y, Keum J, Jo JK, Yun SE, Park SJ, Park YJ, Choi MJ, Kim KS, Kim J. A Novel Kinase Inhibitor AX-0085 Inhibits Interferon-γ-Mediated Induction of PD-L1 Expression and Promotes Immune Reaction to Lung Adenocarcinoma Cells. Cells. 2021 Dec 22;11(1):19.

【4】 Chen CL, Pan QZ, Weng DS, Xie CM, Zhao JJ, Chen MS, Peng RQ, Li DD, Wang Y, Tang Y, Wang QJ, Zhang ZL, Zhang XF, Jiang LJ, Zhou ZQ, Zhu Q, He J, Liu Y, Zhou FJ, Xia JC. Safety and activity of PD-1 blockade-activated DC-CIK cells in patients with advanced solid tumors. Oncoimmunology. 2018 Jan 10;7(4):e1417721.

【5】 Dang AT, Teles RM, Liu PT, Choi A, Legaspi A, Sarno EN, Ochoa MT, Parvatiyar K, Cheng G, Gilliet M, Bloom BR, Modlin RL. Autophagy links antimicrobial activity with antigen presentation in Langerhans cells. JCI Insight. 2019 Apr 18;4(8):e126955.

【6】 Liu B, Bao L, Wang L, Li F, Wen M, Li H, Deng W, Zhang X, Cao B. Anti-IFN-γ therapy alleviates acute lung injury induced by severe influenza A (H1N1) pdm09 infection in mice. J Microbiol Immunol Infect. 2021 Jun;54(3):396-403.

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