Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis

Abstract

Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.

The Role of the Immune System in Cutaneous Squamous Cell Carcinoma

“…Constitutive absence of LC in chemically-induced cSCC appears to inhibit inflammation and mutagenesis required for tumor initiation and progression [37,38]. Conditional depletion of LCs and dDCs has conversely suggested an anticarcinogenic role though TNFα-mediated natural killer (NK) cell recruitment and activation [39,40]. DCs dampen inflammation initially in UVB-damaged murine skin through phagocytosis of apoptotic keratinocytes [41], but they subsequently promote tumor progression in an IL-22- and TGFβ1-dependent manner [31,42].…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…48,261,[267][268][269][270][271][272][273] In this setting, the profiling of T REG cells is being performed in most cases to estimate the ability of cyclophosphamide to specifically target these immunosuppressive cells. [274][275][276] It will be interesting to see whether the peripheral profile (in terms of abundance and activation status) of CD4…”

The role of Langerhans cells in pathologies of the skin

“…Ortner et al . found that LCs cooperate with NK cells to impair oncogenic damage in the DMBA/TPA mouse SCC model . The depletion of either NK cells or LCs in the LangDTR mouse caused the accumulation of DNA‐damaged keratinocytes.…”

“…A single administration of diphtheria toxin to deplete LCs at the time of treatment with the carcinogen 7,12‐dimethylbenzanthacene (DMBA) along with 12‐O‐tetradeconylphorbol‐13‐acetate (TPA) in the DMBA/TPA SCC mouse model results in acceleration of tumor growth during the 12 weeks of the study . This suggests that LCs have a tumor suppressive effect during the initiation phase of cancer development.…”