Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity.
Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Yaron
Y
Carmi
1] School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA [2] School of Medicine, Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Palo Alto, California 94305, USA.
Matthew H
MH
Spitzer
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Ian L
IL
Linde
School of Medicine, Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California 94305, USA.
Bryan M
BM
Burt
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Tyler R
TR
Prestwood
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Nicola
N
Perlman
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Matthew G
MG
Davidson
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Justin A
JA
Kenkel
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Ehud
E
Segal
School of Medicine, Department of Biochemistry, Stanford University, Palo Alto, California 94305, USA.
Ganesh V
GV
Pusapati
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Nupur
N
Bhattacharya
School of Medicine, Department of Pathology, Stanford University, Palo Alto, California 94305, USA.
Edgar G
EG
Engleman
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology*; D007518:Isoantibodies / Q000008:administration & dosage / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D017452:Receptors, IgG / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D007074:Immunoglobulin G; D007518:Isoantibodies; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha