CXCR3 Enhances a T-Cell–Dependent Epidermal Proliferative Response and Promotes Skin Tumorigenesis

Abstract

The chemokine receptor CXCR3 has been proposed to play a critical role in host anti-tumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3 deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis (MCA or DMBA/TPA models). CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3−/− mice implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4+ and CD8+ T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T cell-dependent induction of keratinocyte proliferation.

Interleukin-17D Mediates Tumor Rejection through Recruitment of Natural Killer Cells

“…A recent study showed that the novel chemokine chemerin can recruit NK cells to mediate tumor surveillance (Pachynski et al, 2012), but it remains unclear what induces chemerin during inflammation. The chemokine receptor CXCR3 is expressed on NK cells (Uppaluri et al, 2008) and it ligands ITAC, MIG, and IP-10 can be induced by interferons during tumor development, but this receptor-ligand axis is not involved in the surveillance of MCA-induced sarcomas (Winkler et al, 2011). On the other hand, CXCR3 is thought to be the receptor that mediates the recruitment of cytokine-secreting CD27 high NK cells into lymph nodes (Martin-Fontecha et al, 2004, Watt et al, 2008), and it may be possible that IL-17D can also induce CXCR3 ligands, either directly or indirectly via NK-cell production of IFNγ.…”

Runx3 at the interface of immunity, inflammation and cancer

“…For example, expression of Cxcr3 in T cells [125] and the receptor for advanced glycation end-products RAGE [126] in immune cells, but not in keratinocytes, was found to be required for sustaining TPA-induced infiltration of inflammatory cells, epidermal hyperplasia and tumor promotion. Analysis of the role of Runx3 has shown that while 100% of DMBA/TPA WT ICR mice developed multiple skin papilloma tumors, the degree of inflammation-associated epithelial hyperplasia and the frequency of papilloma-bearing mice were strongly reduced in Runx3 −/− mice [18].…”

IFN-γ–Mediated Downregulation of LXA4 Is Necessary for the Maintenance of Nonresolving Inflammation and Papilloma Persistence

“…Antigen-specific immunity toward mutant Ras or P53 protein fails to eradicate mutant oncogene-expressing epidermal cells and even induces a remarkable enhancement of tumor growth (25,26). T cells can promote papilloma development (21,27,28) and deficiency of CXCR3, an important chemokine receptor for T-cell recruitment, inhibits skin tumorigenesis (29). Antithymocyte serum has no effect on papilloma regression (30).…”