CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation.
Treatment with ionizing radiation (IR) can lead to the accumulation of tumor-infiltrating regulatory T cells (Treg cells) and subsequent resistance of tumors 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 after exposure to IR. In particular, we found that the cyclin-dependent kinase inhibitor CDKN1A (p21) was overexpressed in LCs and that Cdkn1a(-/-) LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and induced an increase in Treg cell numbers upon exposure to IR, but Cdkn1a(-/-) LCs did not. Our findings suggest a means for manipulating the resistance of LCs to IR to enhance the response of cutaneous tumors to radiotherapy.
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Jeremy G
JG
Price
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, New York, USA.
Juliana
J
Idoyaga
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Hélène
H
Salmon
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Brandon
B
Hogstad
Department of Developmental &Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Carolina L
CL
Bigarella
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Developmental &Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Medicine, Division of Hematology, Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Saghi
S
Ghaffari
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Marylene
M
Leboeuf
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Miriam
M
Merad
D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D007801:Langerhans Cells / Q000528:radiation effects*; D051379:Mice; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D011839:Radiation, Ionizing; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000528:radiation effects*; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21