Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients
Circulating tumor cells (CTCs) and the immune infiltration of tumors are closely related to clinical outcomes. This study aimed to verify the influence of stromal lymphocyte infiltration and the immune context of tumor microenvironment on the hematogenous spread and prognosis of 282 chemotherapy naï...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9460 |
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| author | Bozena Smolkova Zuzana Cierna Katarina Kalavska Svetlana Miklikova Jana Plava Gabriel Minarik Tatiana Sedlackova Dana Cholujova Paulina Gronesova Marina Cihova Karolina Majerova Marian Karaba Juraj Benca Daniel Pindak Jozef Mardiak Michal Mego |
| author_facet | Bozena Smolkova Zuzana Cierna Katarina Kalavska Svetlana Miklikova Jana Plava Gabriel Minarik Tatiana Sedlackova Dana Cholujova Paulina Gronesova Marina Cihova Karolina Majerova Marian Karaba Juraj Benca Daniel Pindak Jozef Mardiak Michal Mego |
| author_sort | Bozena Smolkova |
| collection | DOAJ |
| description | Circulating tumor cells (CTCs) and the immune infiltration of tumors are closely related to clinical outcomes. This study aimed to verify the influence of stromal lymphocyte infiltration and the immune context of tumor microenvironment on the hematogenous spread and prognosis of 282 chemotherapy naïve primary BC patients. To detect the presence of mesenchymal CTCs, RNA extracted from CD45-depleted peripheral blood was interrogated for the expression of mesenchymal gene transcripts. Tumor-infiltrating lymphocytes (TILs) were detected in the stromal areas by immunohistochemistry, using CD3, CD8, and CD45RO antibodies. The concentrations of 51 plasma cytokines were measured by multiplex bead arrays. TILs infiltration in mesenchymal CTC-positive patients significantly decreased their progression-free survival (HR = 4.88, 95% CI 2.30–10.37, <i>p</i> < 0.001 for CD3<sup>high</sup>; HR = 6.17, 95% CI 2.75–13.80, <i>p</i> < 0.001 for CD8<sup>high</sup>; HR = 6.93, 95% CI 2.86–16.81, <i>p</i> < 0.001 for CD45RO<sup>high</sup>). Moreover, the combination of elevated plasma concentrations of transforming growth factor beta-3 (cut-off 662 pg/mL), decreased monocyte chemotactic protein-3 (cut-off 52.5 pg/mL) and interleukin-15 (cut-off 17.1 pg/mL) significantly increased the risk of disease recurrence (HR = 4.838, 95% CI 2.048–11.427, <i>p</i> < 0.001). Our results suggest a strong impact of the immune tumor microenvironment on BC progression, especially through influencing the dissemination and survival of more aggressive, mesenchymal CTC subtypes. |
| first_indexed | 2024-03-10T14:07:43Z |
| format | Article |
| id | doaj.art-57523391fcf44b2dacdf79b1a01b0146 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:07:43Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57523391fcf44b2dacdf79b1a01b01462023-11-21T00:31:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124946010.3390/ijms21249460Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer PatientsBozena Smolkova0Zuzana Cierna1Katarina Kalavska2Svetlana Miklikova3Jana Plava4Gabriel Minarik5Tatiana Sedlackova6Dana Cholujova7Paulina Gronesova8Marina Cihova9Karolina Majerova10Marian Karaba11Juraj Benca12Daniel Pindak13Jozef Mardiak14Michal Mego15Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Pathology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovicova 6, 842 15 Bratislava, SlovakiaComenius University Science Park, Ilkovicova 8, 841 04 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, SlovakiaDepartment of Oncosurgery, National Cancer Institute, Klenova 1, 83310 Bratislava, SlovakiaDepartment of Oncosurgery, National Cancer Institute, Klenova 1, 83310 Bratislava, SlovakiaDepartment of Oncosurgery, National Cancer Institute, Klenova 1, 83310 Bratislava, Slovakia2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, SlovakiaCirculating tumor cells (CTCs) and the immune infiltration of tumors are closely related to clinical outcomes. This study aimed to verify the influence of stromal lymphocyte infiltration and the immune context of tumor microenvironment on the hematogenous spread and prognosis of 282 chemotherapy naïve primary BC patients. To detect the presence of mesenchymal CTCs, RNA extracted from CD45-depleted peripheral blood was interrogated for the expression of mesenchymal gene transcripts. Tumor-infiltrating lymphocytes (TILs) were detected in the stromal areas by immunohistochemistry, using CD3, CD8, and CD45RO antibodies. The concentrations of 51 plasma cytokines were measured by multiplex bead arrays. TILs infiltration in mesenchymal CTC-positive patients significantly decreased their progression-free survival (HR = 4.88, 95% CI 2.30–10.37, <i>p</i> < 0.001 for CD3<sup>high</sup>; HR = 6.17, 95% CI 2.75–13.80, <i>p</i> < 0.001 for CD8<sup>high</sup>; HR = 6.93, 95% CI 2.86–16.81, <i>p</i> < 0.001 for CD45RO<sup>high</sup>). Moreover, the combination of elevated plasma concentrations of transforming growth factor beta-3 (cut-off 662 pg/mL), decreased monocyte chemotactic protein-3 (cut-off 52.5 pg/mL) and interleukin-15 (cut-off 17.1 pg/mL) significantly increased the risk of disease recurrence (HR = 4.838, 95% CI 2.048–11.427, <i>p</i> < 0.001). Our results suggest a strong impact of the immune tumor microenvironment on BC progression, especially through influencing the dissemination and survival of more aggressive, mesenchymal CTC subtypes.https://www.mdpi.com/1422-0067/21/24/9460circulating tumor cellstumor-infiltrating lymphocytesprimary breast cancercytokines |
| spellingShingle | Bozena Smolkova Zuzana Cierna Katarina Kalavska Svetlana Miklikova Jana Plava Gabriel Minarik Tatiana Sedlackova Dana Cholujova Paulina Gronesova Marina Cihova Karolina Majerova Marian Karaba Juraj Benca Daniel Pindak Jozef Mardiak Michal Mego Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients International Journal of Molecular Sciences circulating tumor cells tumor-infiltrating lymphocytes primary breast cancer cytokines |
| title | Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients |
| title_full | Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients |
| title_fullStr | Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients |
| title_full_unstemmed | Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients |
| title_short | Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients |
| title_sort | increased stromal infiltrating lymphocytes are associated with the risk of disease progression in mesenchymal circulating tumor cell positive primary breast cancer patients |
| topic | circulating tumor cells tumor-infiltrating lymphocytes primary breast cancer cytokines |
| url | https://www.mdpi.com/1422-0067/21/24/9460 |
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