Claudin-1 modulates the melanoma immune microenvironment to promote tumor growth and is a candidate therapeutic target for advanced melanoma

Malignant cutaneous melanoma is a highly aggressive cancer responsible for the majority of skin cancer-related deaths with increasing prevalence world-wide. While early-stage melanoma can be efficiently treated by surgery, the treatment of advanced melanoma with immune checkpoint (ICT) therapy remains unsatisfactory with a large number of patients displaying intrinsic resistance or developing resistance over time. A key therapeutic challenge is tumour heterogeneity with melanoma cells existing in multiple states with differing proliferative and invasive capacities. The transmembrane protein Claudin-1 (CLDN1) exhibits a dual role as tight junction protein regulating epithelial barrier function and as a regulator of epithelial-to-mesenchymal transition (EMT), a hallmark of fibrotic disease and cancer. Analyses of public TCGA and TIDE patient datasets showed that CLDN1 is preferentially expressed in mesenchymal melanoma cells and correlates with poor survival of metastatic melanoma and of ICT treated patients. In accordance, CLDN1 expression is associated with an immune-depleted tumour microenvironment (TME). Using gain and loss-of-function studies in human melanoma spheroids and xenografts in syngeneic mouse models, we define two critical roles for CLDN1 in melanoma, a requirement for growth of mesenchymal melanoma cells and the ability to reprogram a TME depleted in cytotoxic CD8 T cells that promotes tumour growth. CLDN1 antibody targeting further restored an immune-infiltrated TME to inhibit tumour growth and cooperation with anti-PD-1 ICT. Collectively, our data show that CLDN1 plays an important functional role melanoma and is a candidate target for antibody-based therapies.