Chemical carcinogens and antigens contribute to cutaneous tumor promotion by depleting epidermal Langerhans cells

Epidermal Langerhans cells (LC) are an integral component of the skin immune system as they initiate immune responses to a variety of antigens, including tumor antigens. When skin is exposed to carcinogenic doses of ultraviolet-B irradiation, chemical carcinogens or tumor promoters there is a significant reduction of LC density. This causes the skin to be immunocompromised and provides an opportunity for aberrant cells to escape immune detection and develop into tumors. Consequently LC depletion is a key event associated with the pathogenesis of skin cancer. We propose that LC depletion contributes to tumor promotion and therefore any agents that reduce LC number, e.g. the contact sensitizing antigen 2,4,6-trinitrochlorobenzene (TNCB), may also contribute to tumor promotion. This proposal was evaluated in cutaneous carcinogenesis by treating mouse skin with a tumor initiating dose of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) followed by a tumor promoter. The initiating dose of DMBA did not cause LC depletion or tumor development. However, if the DMBA-treated skin was then exposed to a concentration of TNCB that caused LC depletion, skin tumors developed. This is analogous to the classical initiator/ promoter system with an LC-depleting dose of TNCB contributing to tumor promotion. Further, this promotion effect was independent of the commencement time of the promoter application, as 2% TNCB applied either 1 or 12 weeks after DMBA initiation induced tumor development. Analysis of the association of LC depletion with immunosuppression and tumor promotion, showed that these events were linked, irrespective of the agent that caused the depletion. It is therefore concluded that LC depletion and local immunosuppression are important aspects of tumor promotion in cutaneous carcinogenesis and non-carcinogenic agents may have tumor promoter activities.