CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation

Abstract

Treatment with ionizing irradiation (IR) may lead to accumulation of tumor-infiltrating T regulatory (Treg) 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 Treg cell numbers upon exposure to IR. These findings suggest a means for manipulating LC IR-resistance to increase cutaneous tumor response to radiotherapy.

Exogenous remodeling of lung resident macrophages protects against infectious consequences of bone marrow-suppressive chemotherapy

“…The mechanisms whereby ViMs show more enhanced chemotherapy stability than AMs remain unclear at present. We note that this stability was not linked solely to increased expression of cyclin-dependent kinase inhibitor p21 as was reported in radiation resistance by epidermal Langerhans cells (30).…”

“…4E). Of note, ViM gene expression profiles were not concordant with the signature of epidermal Langerhans cells that are resistant to ionizing irradiation (30) (Fig. S7).…”

Radiotherapy and immune checkpoints inhibitors for advanced melanoma

“…Also CD47 blockade, whose expression on cancer cells suppress innate immunity, may directly enhance tumour immune-surveillance by CD8 T cells; CD47 expression in tumour microenvironment limits the cooperation between anti-tumour T cell immunity and radiation therapy [54]. Recently, it was also shown that radiation induces Langerhans' cells to migrate from the skin to lymph nodes, where they stimulate regulatory T-cells [55,56]. Additionally, counterbalance of the effector phase induced by RT is the increase expression of PD-L1 on cancer cells after radiation, which may de-activate effector T-cells [6].…”

The TAM family as a therapeutic target in combination with radiation therapy

“…Little is known about the relative effects of radiation on the distinct DC subtypes in vivo, but recent studies suggest that multiple DC subtypes are negatively affected. Price et al [22] demonstrated that in the skin of tumor-free mice, both epidermal Langerhans cells and dermal DC are decreased in number following radiation and these cells repopulate ∼10 days following treatment. While Langerhans cells exhibit DNA damage following radiation, they do not undergo cell death, but instead repair DNA damage and migrate to draining lymph nodes where they are more effective at driving T regulatory cell expansion than unirradiated Langerhans cells [22].…”

“…Price et al [22] demonstrated that in the skin of tumor-free mice, both epidermal Langerhans cells and dermal DC are decreased in number following radiation and these cells repopulate ∼10 days following treatment. While Langerhans cells exhibit DNA damage following radiation, they do not undergo cell death, but instead repair DNA damage and migrate to draining lymph nodes where they are more effective at driving T regulatory cell expansion than unirradiated Langerhans cells [22]. These data suggest that radiation therapy effectively causes DC and Langerhans cell migration to draining lymph nodes, but that these drive expansion of suppressive T-cell populations.…”