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.