Modulation of myeloid-derived dendritic cell maturity: unmasking a novel role for the tumor suppressor p15Ink4b in immunity

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	IMMUNO/INFLAM-6

* FARE Award Winner

Authors

• J Fares
• L Wolff
• J Bies

Abstract

The expression of tumor suppressor p15Ink4b (p15) is found to be lost in up to 80% of all acute myeloid leukemia patients. During leukemogenesis, escape of pre-leukemic cells from immune clearance represents an important step in the establishment of leukemia. Dendritic cells (DCs) are the most potent antigen-presenting cells that play a critical role in the regulation of immune responses against pathogens and cancerous cells. However, whether p15 plays a role in DC development has never been addressed. We found that expression of p15 is strongly induced during development and activation of bone marrow-derived DCs (BM-DCs), suggesting an important role for p15 in DC maturation. Myeloid-specific deletion of p15 in mice resulted in significantly fewer and less mature myeloid DCs (mDCs) as compared to wild type mice. Also, BM cells from knockout mice cultured in vitro generated BM-DCs that express lower levels of MHCII and the co-stimulatory molecules CD80 and CD86. Re-expression of p15 resulted in increased expression of both co-stimulatory molecules. Additionally, incomplete maturation of BM-DCs correlated with a reduced ability to activate T cells in an allogeneic MLR. Our study suggests that loss of p15Ink4b in AML affects the maturation and the function of DCs.

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