The cell cycle inhibitor Cdkn1a regulates Langerhans cell radiation resistance and promotes T regulatory cell generation upon exposure to ionizing irradiation

Treatment with ionizing irradiation (IR) may lead to accumulation of tumor-infiltrating T regulatory (T(reg)) cells and subsequent tumor resistance to radiotherapy. Here we focused on the contribution of the epidermal mononuclear phagocytes, Langerhans cells (LCs), to this phenomenon because of their ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage post-IR. Particularly, we found that CDKN1A (cyclin-dependent kinase inhibitor 1A, also known as p21) was overexpressed in LCs, and that Cdkn1a(−/−) LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type, but not Cdkn1a(−/−), LCs up-regulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and increased T(reg) cell numbers upon exposure to IR. These findings suggest a means for manipulating LC IR-resistance to increase cutaneous tumor response to radiotherapy.