Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer
Abstract Background The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their...
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BMC
2024-12-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01932-4 |
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| author | Eunkyung Han Hye Yeon Choi Hyun Jung Kwon Yul Ri Chung Hee-Chul Shin Eun-Kyu Kim Koung Jin Suh Se Hyun Kim Jee Hyun Kim So Yeon Park |
| author_facet | Eunkyung Han Hye Yeon Choi Hyun Jung Kwon Yul Ri Chung Hee-Chul Shin Eun-Kyu Kim Koung Jin Suh Se Hyun Kim Jee Hyun Kim So Yeon Park |
| author_sort | Eunkyung Han |
| collection | DOAJ |
| description | Abstract Background The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs. Methods We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL levels. Results Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56+, CD57+, GNLY+, and GZMB+ TILs not only in absolute number but also in proportion relative to CD4+ or CD8+ TILs. High TIL and its subset (CD4+, CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration. Conclusion Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies. |
| format | Article |
| id | doaj-art-71e00d2dac6249b19ef24b80f17fc3dd |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-71e00d2dac6249b19ef24b80f17fc3dd2024-12-08T12:50:03ZengBMCBreast Cancer Research1465-542X2024-12-0126111510.1186/s13058-024-01932-4Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancerEunkyung Han0Hye Yeon Choi1Hyun Jung Kwon2Yul Ri Chung3Hee-Chul Shin4Eun-Kyu Kim5Koung Jin Suh6Se Hyun Kim7Jee Hyun Kim8So Yeon Park9Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Bundang Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Bundang Hospital, Seoul National University College of MedicinePathology Center, Seegene Medical FoundationDepartment of Surgery, Seoul National University Bundang Hospital, Seoul National University College of MedicineDepartment of Surgery, Seoul National University Bundang Hospital, Seoul National University College of MedicineDivision of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of MedicineDivision of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of MedicineDivision of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of MedicineDepartment of Pathology, Seoul National University Bundang Hospital, Seoul National University College of MedicineAbstract Background The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs. Methods We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL levels. Results Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56+, CD57+, GNLY+, and GZMB+ TILs not only in absolute number but also in proportion relative to CD4+ or CD8+ TILs. High TIL and its subset (CD4+, CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration. Conclusion Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies.https://doi.org/10.1186/s13058-024-01932-4Tumor infiltrating lymphocyteTriple-negative breast cancerCytotoxic T lymphocyteNK cellSpatial distribution |
| spellingShingle | Eunkyung Han Hye Yeon Choi Hyun Jung Kwon Yul Ri Chung Hee-Chul Shin Eun-Kyu Kim Koung Jin Suh Se Hyun Kim Jee Hyun Kim So Yeon Park Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer Breast Cancer Research Tumor infiltrating lymphocyte Triple-negative breast cancer Cytotoxic T lymphocyte NK cell Spatial distribution |
| title | Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer |
| title_full | Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer |
| title_fullStr | Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer |
| title_full_unstemmed | Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer |
| title_short | Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer |
| title_sort | characterization of tumor infiltrating lymphocytes and their spatial distribution in triple negative breast cancer |
| topic | Tumor infiltrating lymphocyte Triple-negative breast cancer Cytotoxic T lymphocyte NK cell Spatial distribution |
| url | https://doi.org/10.1186/s13058-024-01932-4 |
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