Cutaneous squamous cell carcinoma (SCC) is the most prevalent invasive malignancy with metastatic potential.,The epidermis is exposed to a variety of environmental DNA-damaging chemicals, principal among which are polyaromatic hydrocarbons (PAH) ubiquitous in the environment, tobacco smoke, and broiled meats.,Langerhans cells (LC) comprise a network of dendritic cells situated adjacent to basal, suprabasal, and follicular infundibular keratinocytes that when mutated can give rise to SCC, and LC-intact mice are markedly more susceptible than LC-deficient mice to chemical carcinogenesis provoked by initiation with the model PAH, 7,12-dimethylbenz[a]anthracene (DMBA).,LC rapidly internalize and depot DMBA as numerous membrane-independent cytoplasmic foci.,Repopulation of LC-deficient mice using fetal liver LC-precursors restores DMBA-induced tumor susceptibility.,LC expression of p450 enzyme CYP1B1 is required for maximal rapid induction of DNA-damage within adjacent keratinocytes and their efficient neoplastic transformation; however, effects of tumor progression also attributable to the presence of LC were revealed as CYP1B1-independent.,Thus, LC make multifaceted contributions to cutaneous carcinogenesis, including via the handling and metabolism of chemical mutagens.,Such findings suggest a cooperative carcinogenesis role for myeloid-derived cells resident within cancer susceptible epithelial tissues principally by influencing early events in malignant transformation.
Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC.,We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard.,We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants.,We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro.,SCC and TSCC are both associated with significantly higher numbers of CD3+ and CD8+ T cells compared to normal skin.,TSCC showed a higher proportion of Foxp3+ T regs to CD8+ T cells compared to SCC and a lower percentage of IFN-γ producing CD4+ T cells.,TSCC, however, had a higher percentage of IL-22 producing CD8+ T cells compared to SCC.,TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC.,IL-22 induced SCC proliferation in vitro despite serum starvation.,Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression.,Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients.,IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.