ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction.
An important goal of cancer immunology is the identification of antigens associated with tumor destruction. Vaccination with irradiated tumor cells engineered to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. A phase I clinical trial of this vaccination strategy in patients with advanced melanoma demonstrated the consistent induction of dense CD4(+) and CD8(+) T lymphocyte and plasma cell infiltrates in distant metastases, resulting in extensive tumor destruction, fibrosis, and edema. Antimelanoma antibody and cytotoxic T cell responses were associated with tumor cell death. To characterize the targets of these responses, we screened an autologous cDNA expression library prepared from a densely infiltrated metastasis with postvaccination sera from a long-term responding patient. High-titer IgG antibodies detected ATP6S1, a putative accessory unit of the vacuolar H(+)-ATPase complex. A longitudinal analysis of this patient revealed an association between the vaccine-induced increase in antibodies to ATP6S1 and tumor destruction. Three additional vaccinated melanoma patients and three metastatic non-small cell lung carcinoma patients vaccinated with autologous GM-CSF-secreting tumor cells similarly showed a correlation between humoral responses to ATP6S1 and tumor destruction. Moreover, a chronic myelogenous leukemia patient who experienced a complete remission after CD4(+) donor lymphocyte infusions also developed high-titer antibodies to ATP6S1. Lastly, vaccination with GM-CSF-secreting B16 melanoma cells stimulated high-titer antibodies to ATPS1 in a murine model. Taken together, these findings demonstrate that potent humoral responses to ATP6S1 are associated with immune-mediated destruction of diverse tumors.
Hodi
F Stephen
FS
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Schmollinger
Jan C
JC
Soiffer
Robert J
RJ
Salgia
Ravi
R
Lynch
Thomas
T
Ritz
Jerome
J
Alyea
Edwin P
EP
Yang
Jihong
J
Neuberg
Donna
D
Mihm
Martin
M
Dranoff
Glenn
G
D000818:Animals; D000917:Antibody Formation; D015704:CD4 Antigens / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000097:blood / Q000235:genetics / Q000276:immunology*
D015704:CD4 Antigens; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D025262:Vacuolar Proton-Translocating ATPases