HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy
Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we in...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1512942 |
| _version_ | 1818276970408968192 |
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| author | Tiziana Triulzi Luca Forte Viola Regondi Martina Di Modica Cristina Ghirelli Maria Luisa Carcangiu Lucia Sfondrini Andrea Balsari Elda Tagliabue |
| author_facet | Tiziana Triulzi Luca Forte Viola Regondi Martina Di Modica Cristina Ghirelli Maria Luisa Carcangiu Lucia Sfondrini Andrea Balsari Elda Tagliabue |
| author_sort | Tiziana Triulzi |
| collection | DOAJ |
| description | Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway. Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment. |
| first_indexed | 2024-12-12T22:54:06Z |
| format | Article |
| id | doaj.art-f7c38e515dcd42adba9b486f12cd05e3 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-12T22:54:06Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-f7c38e515dcd42adba9b486f12cd05e32022-12-22T00:09:00ZengTaylor & Francis GroupOncoImmunology2162-402X2019-01-018110.1080/2162402X.2018.15129421512942HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacyTiziana Triulzi0Luca Forte1Viola Regondi2Martina Di Modica3Cristina Ghirelli4Maria Luisa Carcangiu5Lucia Sfondrini6Andrea Balsari7Elda Tagliabue8Fondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanUniversità degli Studi di MilanoFondazione IRCCS Istituto Nazionale dei Tumori of MilanFondazione IRCCS Istituto Nazionale dei Tumori of MilanThrough whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway. Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.http://dx.doi.org/10.1080/2162402X.2018.1512942breast cancerher2trastuzumabchemokineccl2immune cells |
| spellingShingle | Tiziana Triulzi Luca Forte Viola Regondi Martina Di Modica Cristina Ghirelli Maria Luisa Carcangiu Lucia Sfondrini Andrea Balsari Elda Tagliabue HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy OncoImmunology breast cancer her2 trastuzumab chemokine ccl2 immune cells |
| title | HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| title_full | HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| title_fullStr | HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| title_full_unstemmed | HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| title_short | HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| title_sort | her2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy |
| topic | breast cancer her2 trastuzumab chemokine ccl2 immune cells |
| url | http://dx.doi.org/10.1080/2162402X.2018.1512942 |
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