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.

CONCLUSION:

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: Gina Mantia-Smaldone, Lukas Ronner, Anne Blair, Victoria Gamerman, Christopher Morse, Sandra Orsulic, Stephen Rubin, Phyllis Gimotty, Sarah Adams
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 133 Issue 3 Pg. 584-90 (Jun 2014) ISSN: 1095-6859 [Electronic] United States
• PMID: 24680909 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (immunology, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Doxorubicin (analogs & derivatives, immunology, pharmacology)
• Female
• Genes, BRCA1
• Humans
• Immunomodulation (drug effects)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Mice
• Ovarian Neoplasms (genetics, immunology)
• Polyethylene Glycols (pharmacology)
• T-Lymphocytes (drug effects, immunology)
• Xenograft Model Antitumor Assays