Roles of the immune system in skin cancer

Abstract

Over the past several decades, there has been increasing interest in understanding the roles of the immune system in the development and progression of cancer. The importance of the immune system in human skin cancer has been long recognized based primarily upon the increased incidence of skin cancers in organ transplant recipients and mechanisms of ultraviolet (UV) radiation-mediated immunomodulation. In this review, we integrate multiple lines of evidence highlighting the roles of the immune system in skin cancer. First, we discuss the concepts of cancer immunosurveillance and immunoediting as they might relate to human skin cancers. We then describe the clinical and molecular mechanisms of skin cancer development and progression in the contexts of therapeutic immunosuppression in organ transplant recipients, viral oncogenesis, and UV radiation-induced immunomodulation with a primary focus on basal cell carcinoma and squamous cell carcinoma. The clinical evidence supporting expanding roles for immunotherapy is also described. Finally, we discuss recent research examining the functions of particular immune cell subsets in skin cancer and how they might contribute to both antitumour and protumour effects. A better understanding of the biological mechanisms of cancer immunosurveillance holds the promise of enabling better therapies.

Figure 1. A Paradigm of Cancer Immunosurveillance

Initially, there are pre-cancerous lesions, such as the illustrated actinic keratosis (upper left), in which elimination may occur due to the killing of altered cells by elements of the immune system. Alternatively, a stage of equilibrium may result where tumour cells and immune cells interact during a period of stable tumour size. During this period, immune cells may select to more aggressive and/or less immunogenic tumour variants. Eventually, perhaps as a result of this process, the tumour expands and continues to grow despite the presence of an immune response. This continued growth can be observed in invasive squamous cell carcinoma which typically does not spontaneously regress (lower right).

Figure 2. Mechanisms of Ultraviolet (UV)-Induced Immunomodulation and Carcinogenesis

UV radiation is absorbed by DNA, trans-UCA, and membrane lipids. This results in multiple effects on DNA (left column), generation of various chemical species (middle column), and changes in various cellular compartments (right column). The production of DNA photoproducts, cis-UCA, reactive oxygen species, and active vitamin D produces a range of additional biological mediators that ultimately result in enhanced DNA damage, DNA mutagenesis, decreased DNA repair, and immunosuppression. These factors conspire to induce carcinogenesis.

Figure 3. Multiple Cancer-Immune Interactions Occur in Skin Cancer

Antigen-specific and non-specific interactions characterise the immune response to cancer as well as tumour-intrinsic adaptations. Those thought to favour tumour development are highlighted in red and those that favour tumour elimination are highlighted in green. The combination of these interactions ultimately dictate the outcome in terms of tumour regression, equilibrium or progression. Lymphocyte responses can be antigen-specific or non-specific. T-cells, macrophages, and DCs can have pro- and anti-tumour effects. Tumour cells may adapt as well by downregulating MHC class I and processing and expression of tumour antigens, and may acquire new mutations or exhibit heterogeneous immunogenicity, enabling immune escape.