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

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.