title: The immunomodulatory effects of pegylated liposomal doxorubicin are amplified in BRCA1--deficient ovarian tumors and can be exploited to improve treatment response in a mouse model.
abstract: OBJECTIVE
  Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers.
  
  
  METHODS
  The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo.
  
  
  RESULTS
  The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice.
  
  
  CONCLUSIONS
  Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations.
authors.affiliation: Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: gina.mantia-smaldone@fccc.edu.
authors.forename: Gina
authors.initials: G
authors.lastname: Mantia-Smaldone
authors.affiliation: Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, 3rd Floor, PCAM, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Ronner
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 501 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Blair
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 501 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gamerman
authors.affiliation: Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, 3rd Floor, PCAM, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Morse
authors.affiliation: Women's Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.affiliation: Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rubin
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 501 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Gimotty
authors.affiliation: Division of Gynecologic Oncology, University of New Mexico Cancer Center, 1201 Camino de Salud NE, 1 University of New Mexico, Albuquerque, NM 87106, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Adams
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology; D011092:Polyethylene Glycols / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: BRCA; Host immunity; Immunomodulation; Ovarian cancer; Pegylated Liposomal Doxorubicin; T cells