Myeloid suppressor cell depletion augments antitumor activity in lung cancer.
Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer.Individual antibody mediated depleti...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3398024?pdf=render |
| _version_ | 1818616795579285504 |
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| author | Minu K Srivastava Li Zhu Marni Harris-White Upendra K Kar Min Huang Ming F Johnson Jay M Lee David Elashoff Robert Strieter Steven Dubinett Sherven Sharma |
| author_facet | Minu K Srivastava Li Zhu Marni Harris-White Upendra K Kar Min Huang Ming F Johnson Jay M Lee David Elashoff Robert Strieter Steven Dubinett Sherven Sharma |
| author_sort | Minu K Srivastava |
| collection | DOAJ |
| description | Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer.Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls.Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion. |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
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| publishDate | 2012-01-01 |
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| spelling | doaj.art-a0ab1d2f0c8840d2b257ab3a69022ed52022-12-21T22:23:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4067710.1371/journal.pone.0040677Myeloid suppressor cell depletion augments antitumor activity in lung cancer.Minu K SrivastavaLi ZhuMarni Harris-WhiteUpendra K KarMin HuangMing F JohnsonJay M LeeDavid ElashoffRobert StrieterSteven DubinettSherven SharmaMyeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer.Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls.Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion.http://europepmc.org/articles/PMC3398024?pdf=render |
| spellingShingle | Minu K Srivastava Li Zhu Marni Harris-White Upendra K Kar Min Huang Ming F Johnson Jay M Lee David Elashoff Robert Strieter Steven Dubinett Sherven Sharma Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS ONE |
| title | Myeloid suppressor cell depletion augments antitumor activity in lung cancer. |
| title_full | Myeloid suppressor cell depletion augments antitumor activity in lung cancer. |
| title_fullStr | Myeloid suppressor cell depletion augments antitumor activity in lung cancer. |
| title_full_unstemmed | Myeloid suppressor cell depletion augments antitumor activity in lung cancer. |
| title_short | Myeloid suppressor cell depletion augments antitumor activity in lung cancer. |
| title_sort | myeloid suppressor cell depletion augments antitumor activity in lung cancer |
| url | http://europepmc.org/articles/PMC3398024?pdf=render |
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