title: Nonblocking Monoclonal Antibody Targeting Soluble MIC Revamps Endogenous Innate and Adaptive Antitumor Responses and Eliminates Primary and Metastatic Tumors.
abstract: OBJECTIVE
  The human tumor-derived soluble MHC I-chain-related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model.
  
  
  METHODS
  We treated the engineered MIC-expressing "humanized" TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms.
  
  
  RESULTS
  A sMIC-neutralizing nonblocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC(+)-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T-cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive.
  
  
  CONCLUSIONS
  Therapy with a sMIC-neutralizing nonblocking anti-MIC mAb can effectuate antitumor immune responses against advanced MIC(+) tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Dai
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina. Cancer Immunology Program, Hollings Cancer Center, Charleston, South Carolina.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina. Cancer Immunology Program, Hollings Cancer Center, Charleston, South Carolina.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Staveley-O'Carroll
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. Cancer Immunology Program, Hollings Cancer Center, Charleston, South Carolina.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. Cancer Immunology Program, Hollings Cancer Center, Charleston, South Carolina. Department of Medicine, University of Washington, Seattle, Washington. wujjd@musc.edu.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Wu
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C098080:MICB antigen