Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity

doi:10.1073/pnas.0603503103

Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity

Department of Medical Oncology and Cancer Vaccine Center, Dana–Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Communicated by Harvey Cantor, Harvard Medical School, Boston, MA, May 3, 2006 (received for review March 8, 2006)

Abstract

The activation of NKG2D on innate and adaptive cytotoxic lymphocytes contributes to immune-mediated tumor destruction. Nonetheless, tumor cell shedding of NKG2D ligands, such as MHC class I chain-related protein A (MICA), results in immune suppression through down-regulation of NKG2D surface expression. Here we show that some patients who respond to antibody-blockade of cytotoxic T lymphocyte-associated antigen 4 or vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte–macrophage colony-stimulating factor generate high titer antibodies against MICA. These humoral reactions are associated with a reduction of circulating soluble MICA (sMICA) and an augmentation of natural killer (NK) cell and CD8⁺ T lymphocyte cytotoxicity. The immunotherapy-induced anti-MICA antibodies efficiently opsonize cancer cells for dendritic cell cross-presentation, which is correlated with a diversification of tumor antigen recognition. The anti-MICA antibodies also accomplish tumor cell lysis through complement fixation. Together, these findings establish a key role for the NKG2D pathway in the clinical activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade and granulocyte–macrophage colony-stimulating factor secreting tumor cell vaccines. Moreover, these results highlight the therapeutic potential of anti-MICA antibodies to overcome immune suppression and effectuate tumor destruction in patients.

Footnotes

*To whom correspondence should be addressed at:
Dana–Farber Cancer Institute, Dana 520C, 44 Binney Street, Boston, MA 02115.
E-mail: glenn_dranoff{at}dfci.harvard.edu
Author contributions: M.J. and G.D. designed research; M.J. and F.S.H. performed research; M.J. and G.D. analyzed data; and M.J. and G.D. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

CTLA-4,

cytotoxic T lymphocyte-associated antigen 4;

GM-CSF,

granulocyte-macrophage colony-stimulating factor;

MICA,

MHC class I chain-related protein A;

sMICA,

soluble MICA;

NK,

natural killer;

PBMC,

peripheral blood mononuclear cell.