title: Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity.
abstract: OBJECTIVE
  Studies have demonstrated that cancer-associated matrix metalloproteinases (MMP) can generate single peptide bond cleavages in the hinge region of immunoglobulin G1 (IgG1). This study investigated the cleavage of endogenous IgGs by MMPs in the tumor microenvironment and the consequences of the IgG hinge cleavage for humoral immunity.
  
  
  METHODS
  We investigated the occurrence of single peptide bond cleaved IgGs (scIgG) in tumor tissues and plasma samples collected from a cohort of breast cancer patients (n = 60). Samples from healthy people (n = 20) were used as the control. Antibody hinge cleavage was detected by multiple assays, including IHC, ELISA, and flow cytometry. A correlation analysis was conducted between scIgG levels and patient clinical parameters.
  
  
  RESULTS
  Levels of scIgGs in tumors were significantly higher than in normal tissues. In addition, scIgG levels in tumors were enriched compared with that in the plasma of the same patients. The appearance of scIgGs in tumor tissues was associated with altered host IgG content and decreased IgG1. Increased tumor scIgGs were found to be positively correlated with adverse clinical factors, such as elevated tumor-associated macrophages, increased expression of MMP9 and other MMPs, and local metastasis to axillary lymph nodes.
  
  
  CONCLUSIONS
  The study contributes to mounting evidence for the presence of hinge-cleaved antibodies with reduced Fc immune effector function in the tumor microenvironment. The results highlight a link between tumor scIgGs and poor patient outcomes, and reveal a component of compromised humoral immunity within tumors that could point to new immunotherapeutic strategies to rescue host immunity.
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Zhiqiang.an@uth.tmc.edu Ningyan.zhang@uth.tmc.edu.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Fan
authors.affiliation: Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Anneliese
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Clinical Pathology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Biologics Research, Biotechnology Center of Excellence, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Brezski
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Byung-Kwon
authors.initials: BK
authors.lastname: Choi
authors.affiliation: Biologics Research, Biotechnology Center of Excellence, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Rycyzyn
authors.affiliation: Biologics Research, Biotechnology Center of Excellence, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: William
authors.initials: W
authors.lastname: Strohl
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Biologics Research, Biotechnology Center of Excellence, Janssen R&D, LLC, Spring House, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Zhiqiang.an@uth.tmc.edu Ningyan.zhang@uth.tmc.edu.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000906:Antibodies; D007074:Immunoglobulin G; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9