title: Myeloid suppressor cell depletion augments antitumor activity in lung cancer.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors: Minu K
authors: MK
authors: Srivastava
authors: Li
authors: L
authors: Zhu
authors: Marni
authors: M
authors: Harris-White
authors: Upendra K
authors: UK
authors: Kar
authors: Upendra
authors: U
authors: Kar
authors: Min
authors: M
authors: Huang
authors: Ming F
authors: MF
authors: Johnson
authors: Jay M
authors: JM
authors: Lee
authors: David
authors: D
authors: Elashoff
authors: Robert
authors: R
authors: Strieter
authors: Steven
authors: S
authors: Dubinett
authors: Sherven
authors: S
authors: Sharma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D009362:Neoplasm Metastasis; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D047368:Tumor Burden; D014611:Vaccination
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010047:Ovalbumin