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Gynecol Oncol. 2014 Jun;133(3):584-90. doi: 10.1016/j.ygyno.2014.03.565. Epub 2014 Mar 27.

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.

Author information

1
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.
2
Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, 3rd Floor, PCAM, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
3
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 501 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA.
4
Women's Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
5
Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
6
Division of Gynecologic Oncology, University of New Mexico Cancer Center, 1201 Camino de Salud NE, 1 University of New Mexico, Albuquerque, NM 87106, USA.

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.

KEYWORDS:

BRCA; Host immunity; Immunomodulation; Ovarian cancer; Pegylated Liposomal Doxorubicin; T cells

PMID:
24680909
DOI:
10.1016/j.ygyno.2014.03.565
[Indexed for MEDLINE]

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