title: Mesothelin, a novel immunotherapy target for triple negative breast cancer.
abstract: Mesothelin is a cell-surface glycoprotein present on mesothelial cells and elicits T cell responses in a variety of cancers including pancreatic, biliary and ovarian cancer. Breast cancer is not known to express mesothelin. We postulated that mesothelin may be a unique tumor-associated antigen in triple negative breast cancer (TNBC), a less common breast cancer subtype which may have been under-represented in prior studies that characterized mesothelin expression. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin-fixed paraffin-embedded archival tumor tissues and confirmed that mesothelin was overexpressed in the majority of TNBC (67 %) but only rarely in <5 % ER(+) or Her2-neu(+) breast cancer, respectively. To determine whether mesothelin may be exploited as a novel immunotherapy target in breast cancer, an in vitro cell killing assay was performed to compare the ability of genetically modified T cells expressing a chimeric antibody receptor (CAR) specific for mesothelin (mesoCAR T cells) or non-transduced T cells to kill mesothelin-expressing primary breast cancer cells. A significantly higher anti-tumor cytotoxicity by mesoCAR T cells was observed (31.7 vs. 8.7 %, p < 0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date.
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA. Julia.tchou@uphs.upenn.edu
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Wang
authors.forename: Ben
authors.initials: B
authors.lastname: Selven
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.forename: Jose
authors.initials: J
authors.lastname: Conejo-Garcia
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vondeheide
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D000090204:Mesothelin; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency; D011960:Receptors, Estrogen / Q000172:deficiency; D011980:Receptors, Progesterone / Q000172:deficiency; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D000090204:Mesothelin; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone