Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma
Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aim...
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MDPI AG
2023-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/24/5767 |
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| author | Kathrin Maitz Paulina Valadez-Cosmes Sofia Raftopoulou Oliver Kindler Melanie Kienzl Hamid Bolouri A. McGarry Houghton Rudolf Schicho Akos Heinemann Julia Kargl |
| author_facet | Kathrin Maitz Paulina Valadez-Cosmes Sofia Raftopoulou Oliver Kindler Melanie Kienzl Hamid Bolouri A. McGarry Houghton Rudolf Schicho Akos Heinemann Julia Kargl |
| author_sort | Kathrin Maitz |
| collection | DOAJ |
| description | Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8<sup>+</sup> cytotoxic T cells and an increase in CD4<sup>+</sup> helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary. |
| first_indexed | 2024-03-08T20:55:30Z |
| format | Article |
| id | doaj.art-341ac169d8cf4519aab8942249400edd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T20:55:30Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-341ac169d8cf4519aab8942249400edd2023-12-22T13:58:49ZengMDPI AGCancers2072-66942023-12-011524576710.3390/cancers15245767Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung AdenocarcinomaKathrin Maitz0Paulina Valadez-Cosmes1Sofia Raftopoulou2Oliver Kindler3Melanie Kienzl4Hamid Bolouri5A. McGarry Houghton6Rudolf Schicho7Akos Heinemann8Julia Kargl9Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaCenter for Systems Immunology, Benaroya Research Center, Seattle, WA 98101, USAHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USADivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaDivision of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, AustriaLung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8<sup>+</sup> cytotoxic T cells and an increase in CD4<sup>+</sup> helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary.https://www.mdpi.com/2072-6694/15/24/5767non-small cell lung cancerdiscoidin domain receptor 1tumor microenvironmentregulatory T cells |
| spellingShingle | Kathrin Maitz Paulina Valadez-Cosmes Sofia Raftopoulou Oliver Kindler Melanie Kienzl Hamid Bolouri A. McGarry Houghton Rudolf Schicho Akos Heinemann Julia Kargl Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma Cancers non-small cell lung cancer discoidin domain receptor 1 tumor microenvironment regulatory T cells |
| title | Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma |
| title_full | Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma |
| title_fullStr | Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma |
| title_full_unstemmed | Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma |
| title_short | Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma |
| title_sort | altered treg infiltration after discoidin domain receptor 1 ddr1 inhibition and knockout promotes tumor growth in lung adenocarcinoma |
| topic | non-small cell lung cancer discoidin domain receptor 1 tumor microenvironment regulatory T cells |
| url | https://www.mdpi.com/2072-6694/15/24/5767 |
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