Hodi, F. StephenSchmollinger, Jan C.Soiffer, Robert J.Salgia, RaviLynch, ThomasRitz, JeromeAlyea, Edwin P.Yang, JihongNeuberg, DonnaMihm, MartinDranoff, Glenn2019-10-172002Hodi, F. S., J. C. Schmollinger, R. J. Soiffer, R. Salgia, T. Lynch, J. Ritz, E. P. Alyea, et al. 2002. “ATP6S1 Elicits Potent Humoral Responses Associated with Immune-Mediated Tumor Destruction.” Proceedings of the National Academy of Sciences 99 (10). Proceedings of the National Academy of Sciences: 6919–24. doi:10.1073/pnas.102025999.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41555741An 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.en-USJournal Article2019-10-1710.1073/pnas.102025999