Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors
Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB res...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/2253436 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832558358059548672 |
|---|---|
| author | Mengqi Zhang Lulu Wang Wan Liu Tian Wang Francesco De Sanctis Lifang Zhu Guizhong Zhang Jian Cheng Qin Cao Jingying Zhou Aldo Tagliabue Vincenzo Bronte Dehong Yan Xianchun Wan Guang Yu |
| author_facet | Mengqi Zhang Lulu Wang Wan Liu Tian Wang Francesco De Sanctis Lifang Zhu Guizhong Zhang Jian Cheng Qin Cao Jingying Zhou Aldo Tagliabue Vincenzo Bronte Dehong Yan Xianchun Wan Guang Yu |
| author_sort | Mengqi Zhang |
| collection | DOAJ |
| description | Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy. |
| format | Article |
| id | doaj-art-01381d5a3efc4892a483de5a5793f051 |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-01381d5a3efc4892a483de5a5793f0512025-02-03T01:32:30ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/2253436Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver TumorsMengqi Zhang0Lulu Wang1Wan Liu2Tian Wang3Francesco De Sanctis4Lifang Zhu5Guizhong Zhang6Jian Cheng7Qin Cao8Jingying Zhou9Aldo Tagliabue10Vincenzo Bronte11Dehong Yan12Xianchun Wan13Guang Yu14School of Basic Medical ScienceDepartment of Hematology and OncologyGuangdong Immune Cell Therapy Engineering and Technology Research CenterDepartment of MedicineDepartment of MedicineGuangdong Immune Cell Therapy Engineering and Technology Research CenterGuangdong Immune Cell Therapy Engineering and Technology Research CenterSchool of Basic Medical ScienceSchool of Biomedical SciencesSchool of Biomedical SciencesGuangdong Immune Cell Therapy Engineering and Technology Research CenterDepartment of MedicineGuangdong Immune Cell Therapy Engineering and Technology Research CenterGuangdong Immune Cell Therapy Engineering and Technology Research CenterSchool of Basic Medical ScienceDespite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.http://dx.doi.org/10.1155/2022/2253436 |
| spellingShingle | Mengqi Zhang Lulu Wang Wan Liu Tian Wang Francesco De Sanctis Lifang Zhu Guizhong Zhang Jian Cheng Qin Cao Jingying Zhou Aldo Tagliabue Vincenzo Bronte Dehong Yan Xianchun Wan Guang Yu Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors Journal of Immunology Research |
| title | Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors |
| title_full | Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors |
| title_fullStr | Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors |
| title_full_unstemmed | Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors |
| title_short | Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors |
| title_sort | targeting inhibition of accumulation and function of myeloid derived suppressor cells by artemisinin via pi3k akt mtor and mapk pathways enhances anti pd l1 immunotherapy in melanoma and liver tumors |
| url | http://dx.doi.org/10.1155/2022/2253436 |
| work_keys_str_mv | AT mengqizhang targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT luluwang targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT wanliu targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT tianwang targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT francescodesanctis targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT lifangzhu targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT guizhongzhang targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT jiancheng targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT qincao targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT jingyingzhou targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT aldotagliabue targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT vincenzobronte targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT dehongyan targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT xianchunwan targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors AT guangyu targetinginhibitionofaccumulationandfunctionofmyeloidderivedsuppressorcellsbyartemisininviapi3kaktmtorandmapkpathwaysenhancesantipdl1immunotherapyinmelanomaandlivertumors |