Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Abstract

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

Keywords: CXC receptors 1 and 2; cancer-associated fibroblast; chemokine; immunotherapy; interleukin-8; microbiome; myeloid-derived suppressor cells; neutrophile; tumor microenvironment.

Figure 1

Various types of components in the TME of solid malignancies. The cellular composition of TME is mainly CAFs, cancer cells, immune cells, and the microbiome. All of the cells interact with each other via soluble molecules such as cytokines or chemokines and trafficking through blood vessels or lymphatic vessels (the abundance of each component is not illustrated here).

Figure 2

The intricate network of the CXCL8-CXCR1/2 axis in TME. CXCL8 binding to CXCR1/2 activates G-protein-mediated signaling cascades in cancer cell. CXCR1/2 activation leads to the dissociation of the Gα subunit from the Gβγ subunits. The signal of Gβγ subunits activate kinase to enhance angiogenesis, proliferation, and invasion. Cancer cell autocrine CXCL8 to recruit MDSCs or neutrophil to TME. Dysbiosis or inflammation affects myeloid cell recruitment through the gut–brain axis.

Figure 3

Small molecule antagonists targeting CXCR1/2. Blocking CXCR1 or CXCR2 impairs immune suppressive cell recruitment and angiogenesis to enhance cancer therapy efficacy.