Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin
α1-antitrypsin (AAT), a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell–dependent immune pathologies. However, AAT does not interfere with isolated T-cell responses; instead, it facilitates polarization...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00559/full |
| _version_ | 1811265618349916160 |
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| author | Ofer Guttman Gabriella Sara Freixo-Lima Ziv Kaner Yotam Lior Peleg Rider Eli C. Lewis |
| author_facet | Ofer Guttman Gabriella Sara Freixo-Lima Ziv Kaner Yotam Lior Peleg Rider Eli C. Lewis |
| author_sort | Ofer Guttman |
| collection | DOAJ |
| description | α1-antitrypsin (AAT), a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell–dependent immune pathologies. However, AAT does not interfere with isolated T-cell responses; instead, it facilitates polarization of macrophages and dendritic cells towards M2-like and tolerogenic cells, respectively. AAT also allows NK cell responses against tumor cells, while attenuating DC-dependent NK cell activities. Since AAT-treated macrophages bear resemblance to cancer-promoting tumor-associated macrophages (TAMs), it became imperative to examine the possible induction of tumor permissive conditions by AAT. Here, AAT treatment is examined for its effect on tumor development, metastatic spread and selected aspects of tumor immunology. Systemic AAT treatment of mice inoculated with B16-F10 melanoma cells resulted in significant inhibition of tumor growth and metastatic spread. Using NK cell–resistant RMA cells, we show that AAT interferes with tumor development in a CD8+ T-cell–dependent manner. Unexpectedly, upon analysis of tumor cellular composition we identified overly active tumor-infiltrating CD8+ T-cells alongside M1-like TAMs in AAT-treated mice. Based on the ability of AAT to undergo chemical modifications, we emulated conditions of elevated reactive nitrogen and oxygen species. Indeed, macrophages were stimulated by treatment with nitrosylated AAT, and IFN transcripts were significantly elevated in tumors extracted soon after ischemia-reperfusion challenge. These context-specific changes may explain the differential effects of AAT on immune responses towards tumor cells versus benign antigenic targets. These data suggest that systemically elevated levels of AAT may accommodate its physiological function in inflammatory resolution, without compromising tumor-targeting immune responses. |
| first_indexed | 2024-04-12T20:27:08Z |
| format | Article |
| id | doaj.art-424d9020d321405794983a8a30fd8d72 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T20:27:08Z |
| publishDate | 2016-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-424d9020d321405794983a8a30fd8d722022-12-22T03:17:51ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-12-01710.3389/fimmu.2016.00559229198Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsinOfer Guttman0Gabriella Sara Freixo-Lima1Ziv Kaner2Yotam Lior3Peleg Rider4Eli C. Lewis5Ben-Gurion UniversityBen-Gurion UniversityBen-Gurion UniversityBen-Gurion UniversityBen-Gurion UniversityBen-Gurion Universityα1-antitrypsin (AAT), a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell–dependent immune pathologies. However, AAT does not interfere with isolated T-cell responses; instead, it facilitates polarization of macrophages and dendritic cells towards M2-like and tolerogenic cells, respectively. AAT also allows NK cell responses against tumor cells, while attenuating DC-dependent NK cell activities. Since AAT-treated macrophages bear resemblance to cancer-promoting tumor-associated macrophages (TAMs), it became imperative to examine the possible induction of tumor permissive conditions by AAT. Here, AAT treatment is examined for its effect on tumor development, metastatic spread and selected aspects of tumor immunology. Systemic AAT treatment of mice inoculated with B16-F10 melanoma cells resulted in significant inhibition of tumor growth and metastatic spread. Using NK cell–resistant RMA cells, we show that AAT interferes with tumor development in a CD8+ T-cell–dependent manner. Unexpectedly, upon analysis of tumor cellular composition we identified overly active tumor-infiltrating CD8+ T-cells alongside M1-like TAMs in AAT-treated mice. Based on the ability of AAT to undergo chemical modifications, we emulated conditions of elevated reactive nitrogen and oxygen species. Indeed, macrophages were stimulated by treatment with nitrosylated AAT, and IFN transcripts were significantly elevated in tumors extracted soon after ischemia-reperfusion challenge. These context-specific changes may explain the differential effects of AAT on immune responses towards tumor cells versus benign antigenic targets. These data suggest that systemically elevated levels of AAT may accommodate its physiological function in inflammatory resolution, without compromising tumor-targeting immune responses.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00559/fullCD8-Positive T-LymphocytesReactive Oxygen Speciesnitrosylationtumor immunologytumor associated macrophages |
| spellingShingle | Ofer Guttman Gabriella Sara Freixo-Lima Ziv Kaner Yotam Lior Peleg Rider Eli C. Lewis Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin Frontiers in Immunology CD8-Positive T-Lymphocytes Reactive Oxygen Species nitrosylation tumor immunology tumor associated macrophages |
| title | Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin |
| title_full | Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin |
| title_fullStr | Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin |
| title_full_unstemmed | Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin |
| title_short | Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin |
| title_sort | context specific and immune cell dependent anti tumor activities of α1 antitrypsin |
| topic | CD8-Positive T-Lymphocytes Reactive Oxygen Species nitrosylation tumor immunology tumor associated macrophages |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00559/full |
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