IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations [TUMOR IMMUNOLOGY]

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. Furthermore, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFN-γ and inhibiting IL-10 production. Neutralizing Ab to IFN-γ, but not IL-17, inhibited nevus development (p < 0.01).

Footnotes

  • 2 L.T. and C.A.E. are coprincipal investigators.

  • This work was supported by Veterans Administration Grant 1I01BX003395 and National Cancer Institute Grant 1R01CA193885 (to C.A.E) and by University of Alabama at Birmingham Comprehensive Cancer Center Grant P30CA013148.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    CHS
    contact hypersensitivity
    dbcAMP
    N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate
    dLN
    draining LN
    DMBA
    7,12-dimethylbenz(a)anthracene
    KO
    knockout
    LN
    lymph node
    qPCR
    quantitative PCR
    SCC
    squamous cell carcinoma
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    UAB
    University of Alabama at Birmingham
    WT
    wild-type.
  • Received August 23, 2016.
  • Accepted November 16, 2016.

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