A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma
Abstract Background Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each divers...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-08-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-021-08636-4 |
| _version_ | 1818729129571254272 |
|---|---|
| author | Monique C. Tavares Cristina D. Sampaio Geraldine E. Lima Victor P. Andrade Daniel G. Gonçalves Mariana P. Macedo Vladmir C. Cordeiro de Lima |
| author_facet | Monique C. Tavares Cristina D. Sampaio Geraldine E. Lima Victor P. Andrade Daniel G. Gonçalves Mariana P. Macedo Vladmir C. Cordeiro de Lima |
| author_sort | Monique C. Tavares |
| collection | DOAJ |
| description | Abstract Background Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. Methods Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. Results We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. Conclusion TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC. |
| first_indexed | 2024-12-17T22:40:59Z |
| format | Article |
| id | doaj.art-b59123e3fd834be4868b10f156142633 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-17T22:40:59Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-b59123e3fd834be4868b10f1561426332022-12-21T21:29:56ZengBMCBMC Cancer1471-24072021-08-0121111210.1186/s12885-021-08636-4A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinomaMonique C. Tavares0Cristina D. Sampaio1Geraldine E. Lima2Victor P. Andrade3Daniel G. Gonçalves4Mariana P. Macedo5Vladmir C. Cordeiro de Lima6Department of Medical Oncology, AC Camargo Cancer CenterDepartment of Medical Oncology, AC Camargo Cancer CenterDepartment of Medical Oncology, AC Camargo Cancer CenterDepartment of Anatomic Pathology, AC Camargo Cancer CenterLaboratory of Bioinformatics, International Center for Teaching and Research AC Camargo Cancer CenterDepartament of Anatomic Pathology, Hospital Sírio LibanêsDepartment of Medical Oncology, AC Camargo Cancer CenterAbstract Background Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. Methods Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. Results We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. Conclusion TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.https://doi.org/10.1186/s12885-021-08636-4Triple-negative breast cancerImmune infiltratePTENCD8FOXP3Survival |
| spellingShingle | Monique C. Tavares Cristina D. Sampaio Geraldine E. Lima Victor P. Andrade Daniel G. Gonçalves Mariana P. Macedo Vladmir C. Cordeiro de Lima A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma BMC Cancer Triple-negative breast cancer Immune infiltrate PTEN CD8 FOXP3 Survival |
| title | A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma |
| title_full | A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma |
| title_fullStr | A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma |
| title_full_unstemmed | A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma |
| title_short | A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma |
| title_sort | high cd8 to foxp3 ratio in the tumor stroma and expression of pten in tumor cells are associated with improved survival in non metastatic triple negative breast carcinoma |
| topic | Triple-negative breast cancer Immune infiltrate PTEN CD8 FOXP3 Survival |
| url | https://doi.org/10.1186/s12885-021-08636-4 |
| work_keys_str_mv | AT moniquectavares ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT cristinadsampaio ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT geraldineelima ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT victorpandrade ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT danielggoncalves ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT marianapmacedo ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT vladmirccordeirodelima ahighcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT moniquectavares highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT cristinadsampaio highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT geraldineelima highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT victorpandrade highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT danielggoncalves highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT marianapmacedo highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma AT vladmirccordeirodelima highcd8tofoxp3ratiointhetumorstromaandexpressionofptenintumorcellsareassociatedwithimprovedsurvivalinnonmetastatictriplenegativebreastcarcinoma |