YAP activation in the skin promotes an inflamed and immunosuppressed microenvironment

Abstract

The success of cancer immunotherapy is highly dependent on the tumour microenvironment. Tumour responsiveness to immune checkpoint inhibitors depends on potentiating cytotoxic T cell activity, but this can be blocked by the presence of immunosuppressive cells in the microenvironment which interfere with normal T cell function. Understanding how to combat immunosuppression and resensitise tumours to immunotherapy, is the focus of current research efforts. The oncogene Yes Associated Protein (YAP) has a well-established role in cancer growth and metastasis. Separate to cancer, there is an emerging role for YAP in the development of chronic inflammatory diseases and fibrosis. Given this, I sought to define the cellular and molecular immune responses driven by YAP hyperactivation in the skin, with the intention of understanding how oncogenic YAP might influence the tumour microenvironment. Two mouse models were characterised, where YAP was constitutively activated in the basal keratinocytes of the epidermis (K5>YAP5SA and K5>Lats1/2-/-). YAP activation resulted in keratinocyte hyperproliferation, thickening of the epidermis and the development of a dermatitis-like skin phenotype. Analysis of the skin immune contexture, facilitated by Flow Cytometry and single cell RNAseq, revealed a strong infiltration of myeloid cells (dominated by neutrophils), with a gene expression profile characteristic of myeloid derived suppressor cells. In the lymphoid compartment, CD4+ T cells and NK+ cells were significantly increased in YAP-activated skin, without a corresponding increase in cytotoxic CD8+ T cells. Infiltrating CD4+ T cell populations included both conventional, helper and immunosuppressive Treg subtypes. Corresponding analyte analysis, performed on plasma from both YAP-activated models, revealed a cytokine profile characteristic of chronic inflammation and immunosuppression. Importantly, in vivo growth of a syngeneic murine melanoma cell line was significantly accelerated when implanted in K5>YAP5SA mice. Taken together, these data identify a non-cell autonomous role for YAP in influencing the immune contexture of the skin, marked by features of cellular and molecular immunosuppression. Furthermore, the protumorigenic potential of the YAP-driven immune contexture, identified here, warrants further investigation in the immune-oncology space. Show more