Sarcoma Eradication by Doxorubicin and Targeted TNF Relies upon CD8 + T-cell Recognition of a Retroviral Antigen

Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a comb...

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Published inCancer research (Chicago, Ill.) Vol. 77; no. 13; pp. 3644 - 3654
Main Authors Probst, Philipp, Kopp, Janine, Oxenius, Annette, Colombo, Mario P, Ritz, Danilo, Fugmann, Tim, Neri, Dario
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research, Inc 01.07.2017
Subjects
Animals
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell recognition
Cytotoxicity
Doxorubicin
Doxorubicin - pharmacology
Female
Fibronectin
Fibrosarcoma
Histocompatibility antigen H-2
Humans
Immunosurveillance
Isoforms
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred BALB C
Retroviridae - immunology
Sarcoma
Sarcoma - drug therapy
Sarcoma - immunology
Sarcoma - pathology
T cell receptors
Tumor cell lines
Tumor cells
Tumor necrosis factor
Tumor Necrosis Factor-alpha - immunology
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Abstract Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8 T-cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8 T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8 T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8 T cells revealed the presence of H-2L /AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. .
AbstractList These findings offer evidence that retroviral genes contribute to tumoral immune surveillance through a process that can be improved by treatment with a TNF derivative and the chemotherapeutic drug doxorubicin.Antibody–cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8+ T-cell–dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8+ T cells revealed the presence of H-2Ld/AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. Cancer Res; 77(13); 3644–54. ©2017 AACR.
These findings offer evidence that retroviral genes contribute to tumoral immune surveillance through a process that can be improved by treatment with a TNF derivative and the chemotherapeutic drug doxorubicin. Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8+ T-cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8+ T cells revealed the presence of H-2Ld/AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. Cancer Res; 77(13); 3644-54. [copy2017 AACR.
Antibody-cytokine complexes may offer new tools to treat cancer. Here we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to re-challenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8+ T cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication. Sequence analysis of T cell receptors of CD8+ T cells revealed the presence of H-2L d /AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immune surveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment.
Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8 T-cell-dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8 T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8 T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8 T cells revealed the presence of H-2L /AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. .
Abstract Antibody–cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of fibronectin (F8-TNF), can be exploited to eradicate sarcomas in immunocompetent mice. We treated mice bearing WEHI-164 fibrosarcoma with a combination of F8-TNF and doxorubicin, curing the majority of treated animals (29/37). Notably, cured mice were resistant to rechallenge not only by WEHI-164 cells but also heterologous C51 or CT26 colorectal tumor cells in a CD8+ T-cell–dependent process. Mechanistic analyses revealed that each tumor cell line presented AH1, a common endogenous retroviral peptide. Numbers of AH1-specific CD8+ T cells exhibiting cytotoxic capacity were increased by F8-TNF plus doxorubicin treatment, arguing that cognate CD8+ T cells contributed to tumor eradication. Sequence analysis of T-cell receptors of CD8+ T cells revealed the presence of H-2Ld/AH1-specific T cells and an expansion of sequence diversity in treated mice. Overall, our findings provide evidence that retroviral genes contribute to tumoral immunosurveillance in a process that can be generally boosted by F8-TNF and doxorubicin treatment. Cancer Res; 77(13); 3644–54. ©2017 AACR.
Author Fugmann, Tim
Kopp, Janine
Probst, Philipp
Oxenius, Annette
Colombo, Mario P
Ritz, Danilo
Neri, Dario
AuthorAffiliation d Philochem AG, Libernstrasse 3, CH-8112 Otelfingen (Switzerland)
c Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
a Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, CH-8093 Zürich (Switzerland)
b Department of Biology, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, CH-8093 Zürich (Switzerland)
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– name: c Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
– name: a Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, CH-8093 Zürich (Switzerland)
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  fullname: Neri, Dario
  email: dario.neri@pharma.ethz.ch
  organization: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland. dario.neri@pharma.ethz.ch
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Snippet Antibody-cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of...
Abstract Antibody–cytokine complexes may offer new tools to treat cancer. Here, we show how TNF-linked antibodies, which recognize tumor-selective splice...
These findings offer evidence that retroviral genes contribute to tumoral immune surveillance through a process that can be improved by treatment with a TNF...
Antibody-cytokine complexes may offer new tools to treat cancer. Here we show how TNF-linked antibodies, which recognize tumor-selective splice isoforms of...
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SubjectTerms Animals
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell recognition
Cytotoxicity
Doxorubicin
Doxorubicin - pharmacology
Female
Fibronectin
Fibrosarcoma
Histocompatibility antigen H-2
Humans
Immunosurveillance
Isoforms
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred BALB C
Retroviridae - immunology
Sarcoma
Sarcoma - drug therapy
Sarcoma - immunology
Sarcoma - pathology
T cell receptors
Tumor cell lines
Tumor cells
Tumor necrosis factor
Tumor Necrosis Factor-alpha - immunology
Title Sarcoma Eradication by Doxorubicin and Targeted TNF Relies upon CD8 + T-cell Recognition of a Retroviral Antigen
URI https://www.ncbi.nlm.nih.gov/pubmed/28484076
https://www.proquest.com/docview/1983251286/abstract/
https://search.proquest.com/docview/1896897784
https://search.proquest.com/docview/1926525532
https://pubmed.ncbi.nlm.nih.gov/PMC5557340
Volume 77
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