Immunopathogenesis and Therapeutic Implications in Basal Cell Carcinoma: Current Concepts and Future Directions.

This review is focused on understanding the reasons why basal cell carcinoma (BCC), the most common, increasingly prevalent cancer, is classified as an "immune excluded" malignancy. It is, despite manifesting one of the highest tumor mutational burdens of any solid human malignancy, considered to be a biomarker of enhanced tumor immunogenicity and efficacy of tumor-targeted immunotherapy. Following a brief clinical overview, the balance of the review addresses important translational issues based on recent insights into the mechanisms underpinning immune exclusion/evasion in BCC. These include, firstly, the role of infectious agents and non-infectious potential causes of predisposition for and/or exacerbation of disease development and progression. Secondly, an overview of existing and emerging novel therapeutic strategies to ameliorate immune exclusion in BCC based on targeting several key immunosuppressive mechanisms. These are (i) inappropriate activation of the hedgehog signaling pathway (HHSP) due to formation of key driver mutations; (ii) interference with the presentation of tumor-specific antigens/neoantigens to cytotoxic T-cells; (iii) attenuation of the influx of anti-tumor natural killer cells; (iv) the recruitment and activation of immune suppressive regulatory T-cells; and (v) localized and systemic immune dysfunction achieved via elevated levels of soluble co-inhibitory immune checkpoint proteins (ICPs). The final section is focused on current and emerging pharmacologic and immune-based therapies.