Chemokines and their receptors play an important role in the recruitment, activation and differentiation of immune cells. The chemokine receptor, CXCR3, and its ligands, CXCL9, CXCL10, and CXCL11 are key immune chemoattractants during interferon-induced inflammatory responses. Inflammation of the skin resulting from infections or autoimmune disease drives expression of CXCL9/10/11 and the subsequent recruitment of effector, CXCR3+ T cells from the circulation. The relative contributions of the different CXCR3 chemokines and the three variant isoforms of CXCR3 (CXCR3A, CXCR3B, CXCR3alt) to the inflammatory process in human skin requires further investigation. In skin cancers, the CXCR3 receptor can play a dual role whereby expression on tumor cells can lead to cancer metastasis to systemic sites while receptor expression on immune cells can frequently promote anti-tumor immune responses. This review will discuss the biology of CXCR3 and its associated ligands with particular emphasis on the skin during inflammation and carcinogenesis.

Highlights d Dysfunctional CD226-negative T cells accumulate in mouse and human tumors d CD155 induces ubiquitination via CBL-B and proteasomal degradation of CD226 d A mutation of Y319 maintains CD226 expression and improves anti-tumor immunity d ICB-therapy in melanoma patients relies on the presence of CD226 + CD8 + T cells

Non-melanoma skin cancer (NMSC), including both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is a commonly diagnosed cancer in Australia. The role of the immune system in the development of NMSC is still poorly understood. Using a mouse model of precancerous, hyperplastic skin, we have investigated the expression and targeting of the T cell co-stimulatory molecule, 4-1BB (CD137). Our data shows that 4-1BB is expressed on both CD8 and non-CD8 T cells isolated from precancerous mouse skin with limited expression on T cells in normal skin or skin-draining lymph nodes. In contrast, the ligand for 4-1BB, 4-1BBL, was poorly expressed in skin and draining lymph nodes from precancerous or normal skin. Intradermal injection of antibodies against 4-1BB was more effective at labelling target cells within the hyperplastic skin than intravenous injection. Agonist antibodies against 4-1BB showed some enhancement of skin T cell function in vitro. The data suggests that 4-1BB expression is upregulated on T cells within precancerous mouse skin and may represent a promising target for immunotherapy against precancerous skin lesions.