Chemotherapy Induces Intra-Tumoral Expression of Chemokines in Cutaneous Melanoma, Favoring T Cell Infiltration and Tumor Control

Abstract

T cell infiltration is known to impact tumour growth and is associated with cancer patient survival. However, the molecular cues that favour T cell infiltration remain largely undefined. Here, using a genetically-engineered mouse model of melanoma, we show that CXCR3 ligands and CCL5 synergize to attract effector T cells into cutaneous metastases, and their expression inhibits tumour growth. In melanoma patients, these chemokines are also up-regulated in chemotherapy-sensitive lesions following chemotherapy, and correlate with T cell infiltration, tumour control and patient survival. Mechanistically, we found that dacarbazine, temozolomide and cisplatin induce expression of these T cell-attracting chemokines in several human melanoma cell lines in vitro. These data identify the induction of intra-tumoral expression of chemokines as a novel cell-extrinsic mechanism of action of chemotherapy that results in the recruitment of immune cells with anti-tumour activity. Additionally, we report a new reporter mouse melanoma model that enables visualization of spontaneous tumour development by in vivo bioluminescence imaging. This model will facilitate testing of future chemo-immunotherapeutic strategies against melanoma.