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Review
. 2018 Feb:63:40-47.
doi: 10.1016/j.ctrv.2017.11.007. Epub 2017 Nov 26.

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy

Ryuma Tokunaga  1 , Wu Zhang  1 , Madiha Naseem  1 , Alberto Puccini  1 , Martin D Berger  1 , Shivani Soni  1 , Michelle McSkane  1 , Hideo Baba  2 , Heinz-Josef Lenz  3
Affiliations
Review

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy

Ryuma Tokunaga et al. Cancer Treat Rev. 2018 Feb.

Abstract

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

Keywords: CXCL10; CXCL11; CXCL9; CXCR3; Cancer; Immunotherapy.

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Conflict of interest statement

Potential Conflicts of Interest Statement: H.-J. Lenz is a consultant/advisory board member for Bayer, Boehringer Ingelheim, Celgene, Merck Serono, and Roche. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1
Figure 1
CXCL9, -10, -11/CXCR3 axis in the tumor environment. CXCL9, -10, and -11 are mainly secreted by monocytes, endothelial cells, fibroblasts, and cancer cells in response to IFN-γ. The work of CXCL9, -10, -11/CXCR3 axis is mainly divided into two directions; paracrine signaling for immune activation and autocrine signaling for proliferation and metastasis of cancer cells. As for paracrine signal, this axis works primarily for immune cell migration, differentiation, and activation. Immune reactivity is occurred with recruitment of CTLs, NK cells, NKT cells, and macrophages through this axis, and Th1 polarization by this axis also activate the immune cells in response to IFN-γ. On the contrary, as for autocrine signal, cancer cells have a propensity to metastasize due to the tumor-derived ligands activity mainly through CXCR3A. Tumor-derived chemokines are also responsible for recruitment of Th2 cells, Tregs, and MDSCs, which play the role of creating a pro-tumoral microenvironment. Abbreviations: CTLs, cytotoxic lymphocytes; NK, natural killer; NKT, natural killer T; MΦ, macrophage; MDSCs, myeloid derived suppressor cells; Th0, naive T; Th1, T helper 1; Th2, T helper 2; Th17, T helper 17; Tregs, regulatory T cell
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