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

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.

Prognostic value of the expression of chemokines and their receptors in regional lymph nodes of melanoma patients

“…CD8‐positive T cells recognize tumour cell antigens and drive anti‐tumour response by secreting effector cytokines, releasing cytotoxic molecules such as granzyme B and perforin, and inducing apoptosis in tumour cells . The CXCL9‐11/CXCR3 axis regulates CD8‐positive T cell migration, differentiation and activation . CD8‐positive T cells express CXCR3 and are capable of invading into tumours when activated by chemokines.…”

“…15 Increased levels of CXCL9-11 are associated with a higher number of CD8-positive T cells infiltrating the tumour, decreased metastatic activity and improved survival of cancer patients. 16 CIBERSORT, an analytical tool for estimating the relative abundance of different cell types based on RNA transcripts, allows calculating cell infiltration in tissues based on gene expression profile data. In comparison with traditional methods, CIBERSORT has the advantage of simultaneous assessment of multiple types of infiltrating cells.…”

“…CD8‐positive T cells express the chemokine receptor CXCR3, which, when bound by the chemokine ligands CXCL9 and 10, drives their migration to the tumour . Increased levels of CXCL9‐11 are associated with a higher number of CD8‐positive T cells infiltrating the tumour, decreased metastatic activity and improved survival of cancer patients …”

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

“…These changes were observed in addition to the upregulation of COX‐2 induction and may have also contributed to the inflammation associated with SUV exposure. CXCL9 and CXCL10 are chemokines that bind to CXCR3 leading to the recruitment of tumor‐suppressive T cells and NK cells into tumor stroma . Higher concentrations of these chemokines in tumors is associated with a higher lymphocyte infiltration and better overall survival in ovarian and other cancers .…”

“…CXCL9 and CXCL10 are chemokines that bind to CXCR3 leading to the recruitment of tumor-suppressive T cells and NK cells into tumor stroma. [85][86][87][88][89] Higher concentrations of these chemokines in tumors is associated with a higher lymphocyte infiltration and better overall survival in ovarian and other cancers. [90][91][92][93][94][95] In contrast, other studies have suggested a protumorigenic role of these two chemokines in cancer progression and metastasis.…”