Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity
S100A9, a multifunctional protein mainly expressed by neutrophils and monocytes, poses an immunological paradox. In virus infections or sterile inflammation, it functions as an alarmin attracting innate immune cells, as well as mediating proinflammatory effects through TLR4 signaling. However, in ca...
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Frontiers Media S.A.
2024-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1479502/full |
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| author | Melike Fusun Demir Melike Fusun Demir Yu-Hsien Lin Pedro Henrique Costa Cruz Masaki Tajima Tasuku Honjo Elisabeth Müller Elisabeth Müller Elisabeth Müller Elisabeth Müller |
| author_facet | Melike Fusun Demir Melike Fusun Demir Yu-Hsien Lin Pedro Henrique Costa Cruz Masaki Tajima Tasuku Honjo Elisabeth Müller Elisabeth Müller Elisabeth Müller Elisabeth Müller |
| author_sort | Melike Fusun Demir |
| collection | DOAJ |
| description | S100A9, a multifunctional protein mainly expressed by neutrophils and monocytes, poses an immunological paradox. In virus infections or sterile inflammation, it functions as an alarmin attracting innate immune cells, as well as mediating proinflammatory effects through TLR4 signaling. However, in cancer, S100A9 levels have been shown to associate with poor prognosis and lack of response to immunotherapy. Its expression by myeloid cells has been related to an immune suppressive phenotype, the so-called myeloid derived suppressor cells (MDSCs). Targeting S100A9 in cancer has therefore been proposed as a potential way to relieve myeloid-mediated immune suppression. Surprisingly, we found that blocking the extracellular TLR4 signaling from S100A9 using the inhibitor Paquinimod, resulted in increased tumor growth and a detrimental effect on anti-PD-L1 efficacy in the CT26 tumor model. This effect was caused by a reduction in the tumor immune infiltration to about half of untreated controls, and the reduction was made up of a 5-fold decrease in Ly6Chigh monocytic cells. The suppressive Ly6G+ myeloid cells compartment was not reduced by Paquinimod treatment, suggesting alternative mechanisms by which S100A9 contributes to myeloid-mediated suppression. Intratumoral injection of recombinant S100A9 early after mice inoculation with CT26 cells had an anti-tumor effect. These findings indicate an important yet understudied role of S100A9 as an alarmin and immune stimulatory signal in cancer settings, and highlight the potential to exploit such signals to promote beneficial anti-tumor responses. |
| format | Article |
| id | doaj-art-b78573aa72d549faa0ad04fa1e73da94 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b78573aa72d549faa0ad04fa1e73da942025-08-20T01:50:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-10-011510.3389/fimmu.2024.14795021479502Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunityMelike Fusun Demir0Melike Fusun Demir1Yu-Hsien Lin2Pedro Henrique Costa Cruz3Masaki Tajima4Tasuku Honjo5Elisabeth Müller6Elisabeth Müller7Elisabeth Müller8Elisabeth Müller9Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, JapanDivision of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto, JapanDivision of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto, JapanDivision of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto, JapanDivision of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto, JapanDepartment of Immunology and Genomic Medicine, Kyoto University, Kyoto, JapanDepartment of Immunology and Genomic Medicine, Kyoto University, Kyoto, JapanDivision of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto, JapanTumor Immunology Group, Institute of Pathology, Oslo University Hospital, Oslo, NorwayTherapy Prediction In Lung Cancer, Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, NorwayS100A9, a multifunctional protein mainly expressed by neutrophils and monocytes, poses an immunological paradox. In virus infections or sterile inflammation, it functions as an alarmin attracting innate immune cells, as well as mediating proinflammatory effects through TLR4 signaling. However, in cancer, S100A9 levels have been shown to associate with poor prognosis and lack of response to immunotherapy. Its expression by myeloid cells has been related to an immune suppressive phenotype, the so-called myeloid derived suppressor cells (MDSCs). Targeting S100A9 in cancer has therefore been proposed as a potential way to relieve myeloid-mediated immune suppression. Surprisingly, we found that blocking the extracellular TLR4 signaling from S100A9 using the inhibitor Paquinimod, resulted in increased tumor growth and a detrimental effect on anti-PD-L1 efficacy in the CT26 tumor model. This effect was caused by a reduction in the tumor immune infiltration to about half of untreated controls, and the reduction was made up of a 5-fold decrease in Ly6Chigh monocytic cells. The suppressive Ly6G+ myeloid cells compartment was not reduced by Paquinimod treatment, suggesting alternative mechanisms by which S100A9 contributes to myeloid-mediated suppression. Intratumoral injection of recombinant S100A9 early after mice inoculation with CT26 cells had an anti-tumor effect. These findings indicate an important yet understudied role of S100A9 as an alarmin and immune stimulatory signal in cancer settings, and highlight the potential to exploit such signals to promote beneficial anti-tumor responses.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1479502/fullS100A9TLR4DAMPmonocytesMDSCTAMs |
| spellingShingle | Melike Fusun Demir Melike Fusun Demir Yu-Hsien Lin Pedro Henrique Costa Cruz Masaki Tajima Tasuku Honjo Elisabeth Müller Elisabeth Müller Elisabeth Müller Elisabeth Müller Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity Frontiers in Immunology S100A9 TLR4 DAMP monocytes MDSC TAMs |
| title | Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity |
| title_full | Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity |
| title_fullStr | Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity |
| title_full_unstemmed | Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity |
| title_short | Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity |
| title_sort | blocking s100a9 signaling is detrimental to the initiation of anti tumor immunity |
| topic | S100A9 TLR4 DAMP monocytes MDSC TAMs |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1479502/full |
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