Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity.
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.
Jinushi
Masahisa
M
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, USA.
Hodi
F Stephen
FS
Dranoff
Glenn
G
D000906:Antibodies / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology; D005260:Female; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D055607:Receptors, Natural Killer Cell
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell