Submitted November 2, 2005
Accepted April 9, 2006
ULBPs, human ligands of the NKG2D receptor, stimulate
tumor immunity; enhancement by IL-15
Claire L Sutherland*, Brian Rabinovich, N Jan Chalupny, Pierre Brawand, Robert Miller, and David Cosman
Department of Oncology, Amgen Inc., Seattle, WA, USA
* Corresponding author; email: sutherlc{at}amgen.com.
ULBPs are human ligands for NKG2D, an activating
receptor expressed on NK, NK1.1+ T cells and T cells.
ULBPs are expressed by a variety of leukemias,
carcinomas, melanomas and tumor cell lines. ULBP
expression correlates with improved survival in cancer
patients, however, the nature of the immune response
that ULBPs elicit is not well understood. We report
that ectopic expression of ULBP1 or ULBP2 on murine EL4
or RMA tumor cells elicits potent anti-tumor responses
in syngeneic C57BL/6 and SCID mice. Although binding of
ULBP3 to murine NKG2D could not be demonstrated in
vitro, ULBP3 can also stimulate anti-tumor
responses, suggesting that ULBP3 binds to murine NKG2D
or possibly another receptor in vivo. ULBP
expression was found to recruit NK, NK1.1+ T cells and T
cells to the tumor. IL-15 was found to strongly enhance
the immune response directed against ULBP-expressing
tumors. Tumors can evade NKG2D immunity by
downregulating expression of NKG2D. Our data suggest
that IL-15 may be useful for overcoming this tumor
evasion strategy. Together, these results demonstrate
that ULBP expression can elicit a potent immune response
and suggest that ULBPs, alone or in combination with IL-
15, can be exploited for anti-tumor therapy.
