Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition
Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-drive...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-06-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1315495 |
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| author | Takuya Osada Michael A. Morse Amy Hobeika Marcio A. Diniz William R. Gwin Zachary Hartman Junping Wei Hongtao Guo Xiao-Yi Yang Cong-Xiao Liu Kensuke Kaneko Gloria Broadwater H. Kim Lyerly |
| author_facet | Takuya Osada Michael A. Morse Amy Hobeika Marcio A. Diniz William R. Gwin Zachary Hartman Junping Wei Hongtao Guo Xiao-Yi Yang Cong-Xiao Liu Kensuke Kaneko Gloria Broadwater H. Kim Lyerly |
| author_sort | Takuya Osada |
| collection | DOAJ |
| description | Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8+ T cells and regulatory CD4+ T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8+ T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition. |
| first_indexed | 2024-12-24T03:25:47Z |
| format | Article |
| id | doaj.art-e1cab1a1d6b840e4b61b5ec0f6c44701 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-24T03:25:47Z |
| publishDate | 2017-06-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-e1cab1a1d6b840e4b61b5ec0f6c447012022-12-21T17:17:21ZengTaylor & Francis GroupOncoImmunology2162-402X2017-06-016610.1080/2162402X.2017.13154951315495Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibitionTakuya Osada0Michael A. Morse1Amy Hobeika2Marcio A. Diniz3William R. Gwin4Zachary Hartman5Junping Wei6Hongtao Guo7Xiao-Yi Yang8Cong-Xiao Liu9Kensuke Kaneko10Gloria Broadwater11H. Kim Lyerly12Duke University Medical CenterDuke University Medical CenterDuke University Medical CenterBiostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer InstituteTumor Vaccine Group, Center for Translational Medicine in Women's Health, University of WashingtonDuke University Medical CenterDuke University Medical CenterDuke University Medical CenterDuke University Medical CenterDuke University Medical CenterDuke University Medical CenterDuke University, Division of Biostatistics Duke Cancer InstituteDuke University Medical CenterExpression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8+ T cells and regulatory CD4+ T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8+ T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.http://dx.doi.org/10.1080/2162402X.2017.1315495adenovirusanti-pd-1anti-pd-l1her2her3immunotherapy |
| spellingShingle | Takuya Osada Michael A. Morse Amy Hobeika Marcio A. Diniz William R. Gwin Zachary Hartman Junping Wei Hongtao Guo Xiao-Yi Yang Cong-Xiao Liu Kensuke Kaneko Gloria Broadwater H. Kim Lyerly Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition OncoImmunology adenovirus anti-pd-1 anti-pd-l1 her2 her3 immunotherapy |
| title | Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition |
| title_full | Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition |
| title_fullStr | Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition |
| title_full_unstemmed | Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition |
| title_short | Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition |
| title_sort | vaccination targeting human her3 alters the phenotype of infiltrating t cells and responses to immune checkpoint inhibition |
| topic | adenovirus anti-pd-1 anti-pd-l1 her2 her3 immunotherapy |
| url | http://dx.doi.org/10.1080/2162402X.2017.1315495 |
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