IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations

Abstract

In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity and metastatic potential. IL-23 was found to be essential for melanocyte homeostasis, whereas IL-12 supported nevus development. A direct action of IL-23 on primary melanocytes, shown to be IL-23R+, demonstrated that DNA repair of damaged melanocytes requires IL-23. Further, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFNγ and inhibiting IL-10 production. Neutralizing antibody to IFNγ, but not IL-17, inhibited nevus development (p<0.01).

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

“…Because of their ability to be recruited to tumors and be activated, NK cells have prominent roles in the immune response to TIS irrespective to the variability in the SASP response of different tumors cells to therapy ( 112 ). Once recruited, NK cells recognize NKG2D and DNAM1 stress ligands upregulated in response to therapy-induced DNA damage and associated TIS ( 113 , 114 ). In addition to stress ligands, TIS cells upregulate adhesion molecules including ICAM-1 which interacts with the CD58 receptor on NK cells to promote tumor cell–NK cell contact—a prerequisite to tumor cell killing ( 115 ) NK cell-mediated toxicity of senescent cells is primarily through the granule exocytosis pathway and not Fas/FASL ( 116 ).…”

Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase‐2

“…Inflammation plays major roles in tumor development and it affects immune responses to therapy. Skin cancer‐associated inflammation involves multiple regulatory pathways, such as interleukin‐induced DNA damage in melanocytes . However, we find that skin cancer induced elevation in the gene and protein expression of NFκB, TNF‐α and IL‐1β.…”

Safety of long‐term interleukin‐23 inhibition in patients with psoriasis

“…Recent research suggests that IL‐23‐related cytokines contribute to the development of basal cell carcinoma . On the other hand, IL‐23 plays a role in DNA repair and is thought to play a role in preventing development of melanoma . This analysis found slightly higher rates of NMSC among patients on guselkumab after crossover from adalimumab, but no melanoma was reported.…”