دورية أكاديمية
Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1.
| العنوان: | Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1. |
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| المؤلفون: | Werfel TA; Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Elion DL; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Rahman B; Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Hicks DJ; Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Sanchez V; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Gonzales-Ericsson PI; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Nixon MJ; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., James JL; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Balko JM; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Scherle PA; Preclinical Biology, Incyte Corporation, Experimental Station, Wilmington, Delaware., Koblish HK; Preclinical Biology, Incyte Corporation, Experimental Station, Wilmington, Delaware., Cook RS; Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Rebecca.cook@vanderbilt.edu.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee. |
| المصدر: | Cancer research [Cancer Res] 2019 Jan 01; Vol. 79 (1), pp. 171-182. Date of Electronic Publication: 2018 Nov 09. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Apoptosis* , Necrosis*, Indoleamine-Pyrrole 2,3,-Dioxygenase/*metabolism , Lung Neoplasms/*pathology , Mammary Neoplasms, Experimental/*pathology , T-Lymphocytes, Regulatory/*pathology , c-Mer Tyrosine Kinase/*metabolism, Animals ; Antineoplastic Agents/pharmacology ; Female ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Lapatinib/pharmacology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/pathology ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/immunology ; Mammary Neoplasms, Experimental/metabolism ; Mice ; Phagocytosis ; Receptor, ErbB-2/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Tumor Microenvironment/immunology ; c-Mer Tyrosine Kinase/genetics |
| مستخلص: | Efferocytosis is the process by which apoptotic cells are cleared from tissue by phagocytic cells. The removal of apoptotic cells prevents them from undergoing secondary necrosis and releasing their inflammation-inducing intracellular contents. Efferocytosis also limits tissue damage by increasing immunosuppressive cytokines and leukocytes and maintains tissue homeostasis by promoting tolerance to antigens derived from apoptotic cells. Thus, tumor cell efferocytosis following cytotoxic cancer treatment could impart tolerance to tumor cells evading treatment-induced apoptosis with deleterious consequences in tumor residual disease. We report here that efferocytosis cleared apoptotic tumor cells in residual disease of lapatinib-treated HER2 + mammary tumors in MMTV-Neu mice, increased immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). Blockade of efferocytosis induced secondary necrosis of apoptotic cells, but failed to prevent increased tumor MDSCs, Treg, and immunosuppressive cytokines. We found that efferocytosis stimulated expression of IFN-γ, which stimulated the expression of indoleamine-2,3-dioxegenase (IDO) 1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO1 in tumor residual disease decreased apoptotic cell- and necrotic cell-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of MMTV-Neu mice. This suggests that apoptotic and necrotic tumor cells, via efferocytosis and IDO1, respectively, promote tumor 'homeostasis' and progression. SIGNIFICANCE: These findings show in a model of HER2 + breast cancer that necrosis secondary to impaired efferocytosis activates IDO1 to drive immunosuppression and tumor progression. (©2018 American Association for Cancer Research.) |
| معلومات مُعتمدة: | P50 CA098131 United States CA NCI NIH HHS; UL1 TR000445 United States TR NCATS NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (IDO1 protein, mouse) 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) 0VUA21238F (Lapatinib) EC 2.7.10.1 (Erbb2 protein, mouse) EC 2.7.10.1 (Mertk protein, mouse) EC 2.7.10.1 (Receptor, ErbB-2) EC 2.7.10.1 (c-Mer Tyrosine Kinase) |
| تواريخ الأحداث: | Date Created: 20181111 Date Completed: 20191021 Latest Revision: 20191218 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1158/0008-5472.CAN-18-1106 |
| PMID: | 30413412 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-18-1106 |