The Role of CXCR3/Ligand Axis in Cancer

CXC chemokines and their receptors (CXCR) influence the tumor microenvironment (TME) by regulating angiogenesis, recruiting activated anti-tumor immune cells and effecting tumor cell proliferation/metastases. The CXCR3/ligand expression in tumors has divergent roles, either promoting or inhibiting tumor growth and metastases. These opposing effects can be explained by the relative differences in tumor CXCR3 receptor isoform expression with CXCR3-A isoform promoting whereas CXCR3-B isoform inhibiting tumor growth. CXCR3/ligand axis recruits immune cells into the TME. The types of leukocytes infiltrating tumors modulate tumor progression. Recruitment of activated T and NK effectors inhibit whereas M2 macrophages and T regulatory cells support tumor growth. Macrophages that lack CXCR3 expression are M2 polarized and promote breast cancer growth. In contrast, the blockade of programmed cell death protein 1 (PD-1) leads to a CXCR3 ligand-mediated recruitment of T cell effectors and better prognosis following adoptive T cell transfer therapy in melanoma. Furthermore, several studies in lung cancer models have shown that enhancing the CXCR3 ligands in the TME following treatment with biological response modifiers recruit innate NK and immune T cell effectors leading to potent anti-tumor activity. This review discusses the tumor supportive and inhibitory role of CXCR3/ligand axis in several cancer types to show the significance of the axis in the modulation of tumor growth. A full comprehension of these mechanisms will be critical for the development of effective CXCR3 targeted strategies against cancer.