ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction

Hodi, F. Stephen; Schmollinger, Jan C.; Soiffer, Robert J.; Salgia, Ravi; Lynch, Thomas J.; Ritz, Jérôme; Alyea, Edwin P.; Yang, Jihong; Neuberg, Donna; Mihm, Martín C.; Dranoff, Glenn

doi:10.1073/pnas.102025999

Cited by 45 publications

(48 citation statements)

References 40 publications

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“…Humoral reactivity was reported against proangiogenic cytokines such as angiopoietin-1 and -2 blocking the endothelial cell tube formation and/or macrophage inhibitory factor attenuating macrophage Tie-2 and MMP9 expression. 35 Likewise, antibodies against protein disulfide isomerases (PDI, ERp5, 37 ) or an accessory unit of the vacuolar H þ -ATPase complex 38 appeared of clinical significance. These data are in line with other observations, stating that the presence of tertiary lymphoid organogenesis (TLO), high endothelial venules (HEV) or germinal centers (GC) residing around the tumor nests are associated with good prognosis in breast carcinoma, non-small cell lung cancer and melanoma.…”

Section: Discussionmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

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Section: Discussionmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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“…Intriguingly, the peak reactivity to ATP6S1 was temporally associated with the development of erythema and hemorrhage in a subcutaneous metastasis. Further investigation disclosed an association between vaccine-stimulated humoral responses to ATP6S1 and tumor destruction in several other immunized metastatic melanoma patients (Hodi et al, 2002).…”

Section: Target Antigensmentioning

confidence: 99%

“…A melanoma cell line was generated from a densely infiltrated metastasis and used to construct a cDNA expression library that was screened with postvaccination serum (Hodi et al, 2002). One of the gene products revealed by this work was ATP6S1, a putative subunit of the ubiquitous vacuolar H + -ATPase complex (Supek et al, 1994).…”

Section: Target Antigensmentioning

confidence: 99%

GM-CSF-secreting melanoma vaccines

2003

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“…26 In brief, total RNA was isolated using guanidine isothiacyanate, mRNA purified over oligo-dT cellulose columns, and cDNA synthesized with Superscript II Reverse Transcriptase (RT; Invitrogen, Carlsbad, CA). The cDNA was cloned into the Lambda Zap vector, and the library was screened according to the manufacturer's instructions (ZAP-cDNA Gigapack III Gold cloning and picoBlue Immunoscreening kits; Stratagene, La Jolla, CA).…”

Section: Cdna Library Construction and Screeningmentioning

confidence: 99%

“…25 Likewise, humoral responses to ATP6S1, a putative accessory unit of the vacuolar H ϩ -ATPase complex, were correlated with clinical benefits in some patients, while this gene product was also targeted by vaccination with GM-CSF-secreting B16 melanoma cells in a murine model. 26 Based upon the induction of high-titer antibodies to ATP6S1 as a function of immunotherapy in both humans and mice, we wondered whether a detailed analysis of vaccine reactions in a murine tumor model might uncover specific gene products that would prove relevant to the evaluation of anti-tumor immunity in patients. Toward this end, we characterized the antigens that elicited humoral responses after tumor cell vaccination in the RENCA murine renal cell carcinoma model.…”

Section: Introductionmentioning

confidence: 99%

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

Fonseca

Soiffer

et al. 2009

Blood

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The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinoma cDNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were

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ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction

Cited by 45 publications

References 40 publications

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

GM-CSF-secreting melanoma vaccines

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

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