Academic Journal
Breast cancer derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment
| العنوان: | Breast cancer derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment |
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| المؤلفون: | Su, Xinming, Xu, Yalin, Fox, Gregory C, Xiang, Jingyu, Kwakwa, Kristin A, Davis, Jennifer L, Belle, Jad I, Lee, Wen-Chih, Wong, Wing H, Fontana, Francesca, Hernandez-Aya, Leonel, Kobayashi, Takayuki, Tomasson, Helen M, Su, Junyi, Bakewell, Suzanne J, Stewart, Sheila A, Egbulefu, Christopher, Karmakar, Partha, Meyer, Melissa A, Veis, Deborah J, DeNardo, David G, Lanza, Gregory M, Achilefu, Samuel, Weilbaecher, Katherine N |
| المصدر: | Open Access Publications |
| بيانات النشر: | Digital Commons@Becker |
| سنة النشر: | 2021 |
| المجموعة: | Washington University School of Medicine: Digital Commons@Becker |
| الوصف: | Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (Arg-1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular L-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor derived GM-CSF as the primary regulator of myeloid cell Arg-1 expression and local immune suppression through a gene knockout screen of breast tumor cell-produced factors. The induction of myeloid cell Arg-1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3, p38 MAPK, and acid signaling through cAMP were required to activate myeloid cell Arg-1 expression in a STAT6 independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host anti-tumor immunity, driving a significant accumulation of Arg-1 expressing myeloid cells compared to lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T-cell therapy and immune checkpoint blockade. Taken together, breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell Arg-1 expression and can be targeted to enhance breast cancer immunotherapy. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | https://digitalcommons.wustl.edu/open_access_pubs/10918; https://digitalcommons.wustl.edu/context/open_access_pubs/article/11910/viewcontent/BreastCancerDerivedGM_CSFRegulatesArginase1InMyeloidCells.pdf; https://digitalcommons.wustl.edu/context/open_access_pubs/article/11910/filename/0/type/additional/viewcontent/Supp_Table_JCI145296.pdf |
| DOI: | 10.1172/JCI145296 |
| الاتاحة: | https://digitalcommons.wustl.edu/open_access_pubs/10918 https://doi.org/10.1172/JCI145296 https://digitalcommons.wustl.edu/context/open_access_pubs/article/11910/viewcontent/BreastCancerDerivedGM_CSFRegulatesArginase1InMyeloidCells.pdf https://digitalcommons.wustl.edu/context/open_access_pubs/article/11910/filename/0/type/additional/viewcontent/Supp_Table_JCI145296.pdf |
| رقم الانضمام: | edsbas.F78E961E |
| قاعدة البيانات: | BASE |
| DOI: | 10.1172/JCI145296 |
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