Abstract
Simple SummaryCutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Immunosuppression raises cSCC incidence rates, while high immunogenicity of the cutaneous tissue enables topical immunotherapy. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets. These clinical observations prompted us to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.
Highlights
Introduction and Overview Cutaneous Squamous CellCarcinoma in the Age of ImmunotherapyCutaneous neoplasms, benign or malign, are defined as aberrantly accumulated patches of mutated or altered cells [1,2]
The immune system is the site of various genotoxic stresses that occur during immune system maturation and immune responses [51]; DNA-altering mechanisms are important in the development of T and B cells, as observed in V(D)J recombination, immunoglobulin class switch recombination and the generation of somatic hypermutations [52,53]
Because defective epidermal differentiation is a hallmark feature of malignant progression [13] that reduces the response to programmed death-1 (PD-1) blockade [18], we started to suspect that the superior outcome of PD-1 blockade in patients with Cutaneous squamous cell carcinoma (cSCC) may be attributable to the primary location of the tumor, namely the skin, which is covered by the stratum corneum (SC) [201]
Summary
Basal cell carcinoma (BCC) and cSCC, which are often referred to as keratinocyte (KC) cancer in aggregation [21], are the most common skin cancers globally, and cSCC is the second most common skin cancer [22]. Because most cSCC cases tend to be metachronous but nonlethal [13,23], this entity is often excluded from cancer registries, and most statistical data are based on surveys or treatment data from subsets of national populations [24]. Based on the cSCC incidence in dark-skinned people (African and Asian heritage), high ambient ultraviolet (UV) radiation (UVR) levels confer greater risk [24]. Poorly differentiated cSCC (desmoplastic/spindle cell/sarcomatoid variant) acquires ex-. Skin cancer tissue comprises tumor cells and stromal responses, and malignant biological behaviors of skin neoplasms can be differentiated on the basis of appearance [33]. Well-differentiated verrucous carcinoma harbors low metastatic potential, whereas highly infiltrative desmoplastic cSCC possesses higher risks of recurrence and metastasis [13]
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