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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

      Highlights

      • BRCA1 dysfunction alters the immunophenotype of ovarian cancer cells.
      • BRCA1− tumors are susceptible to immunomodulation by PLD.
      • BRCA1 ovarian cancer patients are candidates for PLD combined with immunotherapy.

      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

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