Immunomics in Skin Cancer - Improvement in Diagnosis, Prognosis and Therapy Monitoring

Abstract

This review will focus on the elements of the skin's immune system, immune cells and/or non-immune cells that support immune mechanisms, molecules with immune origin and/or immune functions that are involved in skin carcinogenesis. All these immune elements are compulsory in the development of skin tumors and/or sustainability of the neoplastic process. In this light, recent data gathered in this review will acknowledge all immune elements that contribute to skin tumorigenesis; moreover, they can serve as immune biomarkers. These immune markers can contribute to the diagnostic improvement, prognosis forecast, therapy monitoring, and even personalized therapeutical approach in skin cancer. Immune processes that sustain tumorigenesis in non-melanoma and melanoma skin cancers are described in the framework of recent data.

Keywords: Basal cell carcinoma; immunomics; lymphoma; melanoma; squamous cell carcinoma..

Fig. (1)

Immune mechanisms that sustain BCC tumorigenesis. There are several mechanisms that conjoin in skin tumorigenesis in BCC: (1) inconsistent expression of HLA-ABC (MHC l), complete lack of HLA-DR on BCC. (2) absence of costimulatory molecules, ICAM-1, CD40 and CD80, on BCC cells that can induce T cell anergy when TCR-MHC interaction occurs. (3) BCC cells can produce IL-l0, cytokine that can account for the lack of HLA-DR, ICAM-1, CD40 and CD80 and the inconsistent expression of HLA-ABC (4) on BCC cells and the induction of T cell anergy (5). IL-10 moreover reduces the production of pro-inflammatory cytokines, such as IFN-gamma by T cells (6) and the down-regulation of IFN-gamma specific receptors on the BCC tumor cells. (7). Shedding ICAM-1 in the environment can trap T lymphocytes and hinder an eventual tumor cell-T interaction (adapted from [41]).

Fig. (2)

Th1-Th2 physiological balance. When immunity is equilibrated Th1 and Th2 mediated processes are in equilibrium. Tumorigenesis is favored when Th1 surpasses Th2, hence pro-inflammatory cytokines prevail: IFNgamma, TNFalpha, IL-2, 12, 23. If Th2 surpasses Th1 humoral immunity controls the response and anti-inflammatory cytokines: IL-4, 5, 6, 10 can favor autoimmunity. Th1 and Th2 can be generated from null T helpers upon IL-12 and respectively IL-4 action.

Fig. (3)

Immune suppression developed in melanoma tumor (copyright permission for reproduction from [74]. Macrophages secrete indoleamine 2,3-dioxygenase (IDO) that induce an inhibition of T cell proliferation due to tryptophan depletion (acti-vation). Moreover IDO recruits regulatory T cells (FOXP3+) at the tumoral site. Recruiting more TGF beta-secreting Tregs the suppression induced on the effector couple CD4-CD8 increases and therefore the control of tumor development decreases. Tumoral cells by themselves secrete TGFbeta, IL-10, VEGF, PGE2 that induce DCs to secrete more TGFbeta contributing to the conversion of CD4+ T cells to Tregs phenotype enhancing the cellular immune suppression (conversion). Skin-homing T cells CC-chemokine receptor 4 (CCR4) binds to the CCL22 (macrophage-derived chemokine) of the tumor associated macrophages (TAM) and are recruited to the tumoral site (recruitment). On the whole, a favorable microenvironment is created by the concerted action that has as a result the proliferation of Tregs that hinder the cooperation CD4+-CD8+ and therefore abolishes the effector activity of anti-tumoral cytotoxic cells.