Melanoma and autoimmunity: spontaneous regressions as a possible model for new therapeutic approaches

Abstract

Until now, malignancy has been considered a cellular problem represented by the perturbed (uncontrolled) division of the cells associated with invasion and metastasis. Contrary to this classical approach, a new perspective suggests that cancerous disease is, in fact, a supracellular problem represented by inadequate evolution of complex supracellular processes (embryogenesis, development, regeneration, etc.). Such complex processes would be disconnected from the real needs of the body, inducing unnecessary or even dangerous events such as an exacerbated rate of the cell division, angiogenesis, immunosuppression (specific to embryogenesis and melanoma), invasion (mediated by trophoblastic/placental factors in melanoma), and migration (specific to neural crest cells, which generate melanocytes – the most common origin for melanoma). As a result, a correct and comprehensive interpretation of cancer (causes, evolution, therapy, and prevention) should be conducted from a supracellular perspective. After presenting the supracellular perspective, this article further investigates the favorable evolution of malignant melanoma in two distinct situations: in patients receiving no therapy and in patients treated with immune-checkpoint inhibitors. In patients receiving no therapy, spontaneous regressions of melanoma could be the result of several autoimmune reactions (inducing not only melanoma regression but also vitiligo, an autoimmune event frequently associated with melanoma). Patients treated with immune-checkpoint inhibitors develop similar autoimmune reactions, which are clearly correlated with better therapeutic results. The best example is vitiligo, which is considered a positive prognostic factor for patients receiving immune-checkpoint inhibitors. This finding indicates that immune-checkpoint inhibitors induce distinct types of autoimmune events, some corresponding to specific favorable autoimmune mechanisms (favoring tumor regression) and others to common unfavorable adverse reactions (which should be avoided or minimized). In conclusion, the spectrum of autoimmune reactions induced by immune-checkpoint inhibitors should be restricted in the near future to only these specific favorable autoimmune mechanisms. In this way, the unnecessary autoimmune reactions/autoaggressions could be avoided (a better quality of life), and treatment specificity and efficiency should increase (a higher response rate for melanoma therapy).

Melanoma and Vitiligo: In Good Company

“…A remarkable aspect of vitiligo is its relationship with cutaneous melanoma. Melanoma-associated leukoderma spontaneously occurs in a fraction of melanoma patients and correlates with a favorable prognosis [26]. A retrospective study indicated that melanoma patients with concomitant leukoderma had a higher survival rate [29].…”

“…However, responses to these therapies are still suboptimal; around 20% for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and 30-40% for PD-1 or PD-L1-targeting monoclonal antibodies, reaching 60% when the two therapies are combined [23,24]. Autoimmune skin reactions are common irAEs of treatment with check-point inhibitors, and development of leukoderma has been associated with a good outcome due to response to therapy [25,26].…”

Susceptibility and Resistance Mechanisms During Photodynamic Therapy of Melanoma

“…It was postulated that direct mitochondrial and vascular injury induced by BCA-PDT may account for the immediate cause of tumor necrosis (53). Similarly, Zilberstein et al tested the effects of bacteriochlorophyll-serine (Bchl-Ser)-PDT in Nude CD1 mice bearing malignant M2R melanotic melanoma xenografts (76-212 mm 3 ). Primary vascular damage with occlusive thrombi, hemorrhage, and tumor necrosis were confirmed by histopathology.…”

“…Treatment of melanoma continues to face serious challenges, resulting in an increased annual global incidence of 3% (1). Melanoma typically occurs in the skin, but can also develop in other tissues that originate from pigmented neural crest (NC) cells, including the eyes, nasal cavity, anal canal, digestive tract, and genitourinary tract (2,3). Although melanoma accounts for only 2% of all skin cancer cases, it is responsible for 80% of deaths from dermatologic cancers (4).…”

Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy

“…In patients with metastatic melanoma, vitiligo is associated with improved overall survival (OS) [5]. The combination of antitumor immunity (i.e., spontaneous regression) and autoimmunity (i.e., vitiligo) in patients with melanoma is considered an effective immune response against melanocytic cells [6].…”