CXCL9, a C-X-C motif chemokine ligand, lacks glutamic acid-leucine-arginine (ELR). It is closely related to CXCL10 and CXCL11 and binds to the CXCR3 receptor. CXCL9 is strongly induced by interferon gamma (IFN-γ) and is involved in Th1-type response, playing a role in lymphocyte chemotaxis [1]. It is part of the IFN-γ-CXCL9/CXCL10-CXCR3 signaling axis, which has significant implications in various biological processes and diseases [3].

In lung cancer, intratumoral vaccination with CXCL9-engineered dendritic cells enhances T cell infiltration and activation in the tumor microenvironment and improves the efficacy of immune checkpoint blockade, depending on CD4+ and CD8+ T cells as well as CXCR3-dependent T cell trafficking [2]. In vitiligo, the IFN-γ-CXCL9/CXCL10-CXCR3 axis is crucial for the recruitment of autoimmune CXCR3+ CD8+ T cells that destroy melanocytes [3]. In acute interstitial nephritis, urinary CXCL9 is 7.6-fold higher in patients, making it a potential diagnostic biomarker [4]. In cancer, CXCL9-expressing tumor-associated macrophages regulate the recruitment and positioning of CXCR3-expressing stem-like CD8 T cells, influencing anti-PD(L)-1 treatment responses [5]. Also, the CXCL9/10/11-CXCR3 axis affects the tumor microenvironment, tumor growth, metastasis, and immunotherapy resistance [6]. In ovarian cancer, blockade of C5a receptor enhances CXCL9-dependent CD8+ T cell activity by reprogramming macrophages [7].

In conclusion, CXCL9 is a key chemokine involved in Th1-type response, lymphocyte chemotaxis, and various disease processes. Its role in cancer, vitiligo, and acute interstitial nephritis, as revealed through different research models, highlights its importance in understanding disease mechanisms and developing potential diagnostic and therapeutic strategies.

References:

1. Koper, Olga M, Kamińska, Joanna, Sawicki, Karol, Kemona, Halina. . CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. In Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 27, 849-856. doi:10.17219/acem/68846. https://pubmed.ncbi.nlm.nih.gov/29893515/

2. Lim, Raymond J, Salehi-Rad, Ramin, Tran, Linh M, Dubinett, Steven M, Liu, Bin. 2024. CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer. In Cell reports. Medicine, 5, 101479. doi:10.1016/j.xcrm.2024.101479. https://pubmed.ncbi.nlm.nih.gov/38518770/

3. Liu, Hanqing, Wang, Yihui, Le, Qianqian, Tong, Jiajia, Wang, Honglin. 2024. The IFN-γ-CXCL9/CXCL10-CXCR3 axis in vitiligo: Pathological mechanism and treatment. In European journal of immunology, 54, e2250281. doi:10.1002/eji.202250281. https://pubmed.ncbi.nlm.nih.gov/37937817/

4. Moledina, Dennis G, Obeid, Wassim, Smith, Rex N, Wilson, F Perry, Parikh, Chirag R. 2023. Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis. In The Journal of clinical investigation, 133, . doi:10.1172/JCI168950. https://pubmed.ncbi.nlm.nih.gov/37395276/

5. Marcovecchio, Paola Marie, Thomas, Graham, Salek-Ardakani, Shahram. . CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer. In Journal for immunotherapy of cancer, 9, . doi:10.1136/jitc-2020-002045. https://pubmed.ncbi.nlm.nih.gov/33637602/

6. Pan, Minjie, Wei, Xiaoshan, Xiang, Xuan, Zhou, Qiong, Yang, Weibing. 2023. Targeting CXCL9/10/11-CXCR3 axis: an important component of tumor-promoting and antitumor immunity. In Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 25, 2306-2320. doi:10.1007/s12094-023-03126-4. https://pubmed.ncbi.nlm.nih.gov/37076663/

7. Luan, Xiaojin, Lei, Ting, Fang, Jie, Qi, Hongbo, Fu, Yong. 2023. Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 469-489. doi:10.1016/j.ymthe.2023.12.010. https://pubmed.ncbi.nlm.nih.gov/38098230/