Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies
Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-02-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1386828 |
| _version_ | 1819064287003410432 |
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| author | Marie Kostine Inge H. Briaire-de Bruijn Arjen H. G. Cleven Carly Vervat Willem E. Corver Marco W. Schilham Els Van Beelen Hester van Boven Rick L. Haas Antoine Italiano Anne-Marie Cleton-Jansen Judith V. M. G. Bovée |
| author_facet | Marie Kostine Inge H. Briaire-de Bruijn Arjen H. G. Cleven Carly Vervat Willem E. Corver Marco W. Schilham Els Van Beelen Hester van Boven Rick L. Haas Antoine Italiano Anne-Marie Cleton-Jansen Judith V. M. G. Bovée |
| author_sort | Marie Kostine |
| collection | DOAJ |
| description | Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14+ monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163+ macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1+ tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival (p = 0.003) and disease-specific survival (p = 0.041). In vitro, CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors. |
| first_indexed | 2024-12-21T15:28:10Z |
| format | Article |
| id | doaj.art-5f5612669cb946338c1500e09e6fb0fe |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-21T15:28:10Z |
| publishDate | 2018-02-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-5f5612669cb946338c1500e09e6fb0fe2022-12-21T18:58:51ZengTaylor & Francis GroupOncoImmunology2162-402X2018-02-017210.1080/2162402X.2017.13868281386828Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategiesMarie Kostine0Inge H. Briaire-de Bruijn1Arjen H. G. Cleven2Carly Vervat3Willem E. Corver4Marco W. Schilham5Els Van Beelen6Hester van Boven7Rick L. Haas8Antoine Italiano9Anne-Marie Cleton-Jansen10Judith V. M. G. Bovée11Leiden University Medical CenterLeiden University Medical CenterLeiden University Medical CenterLeiden University Medical CenterLeiden University Medical CenterLeiden University Medical CenterLeiden University Medical CenterNetherlands Cancer Institute – Antoni van LeeuwenhoekNetherlands Cancer Institute – Antoni van LeeuwenhoekInstitut BergoniéLeiden University Medical CenterLeiden University Medical CenterBackground: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14+ monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163+ macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1+ tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival (p = 0.003) and disease-specific survival (p = 0.041). In vitro, CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors.http://dx.doi.org/10.1080/2162402X.2017.1386828leiomyosarcomatumor-associated macrophagestumor-infiltrating lymphocyteshlapd-l1, immunotherapy |
| spellingShingle | Marie Kostine Inge H. Briaire-de Bruijn Arjen H. G. Cleven Carly Vervat Willem E. Corver Marco W. Schilham Els Van Beelen Hester van Boven Rick L. Haas Antoine Italiano Anne-Marie Cleton-Jansen Judith V. M. G. Bovée Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies OncoImmunology leiomyosarcoma tumor-associated macrophages tumor-infiltrating lymphocytes hla pd-l1, immunotherapy |
| title | Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| title_full | Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| title_fullStr | Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| title_full_unstemmed | Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| title_short | Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| title_sort | increased infiltration of m2 macrophages t cells and pd l1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies |
| topic | leiomyosarcoma tumor-associated macrophages tumor-infiltrating lymphocytes hla pd-l1, immunotherapy |
| url | http://dx.doi.org/10.1080/2162402X.2017.1386828 |
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