Liposomal Doxorubicin, but Not Platinum-Taxane, Supports MHC-II Expression and Immune Maturation in the Ovarian Tumor Microenvironment

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BACKGROUND: Ovarian cancer is an immunologically cold tumor that is treated with surgery and a chemotherapy regimen of platinum agents with taxanes. Paradoxically, elevated levels of several immune markers are effective at predicting prognosis for patients with ovarian cancer, though it is not clear how chemotherapy might influence this. Chemotherapy elicits immunogenic cell death, yet tumor-controlling doses of chemotherapy are also immunotoxic. OBJECTIVES: To evaluate interactions of chemotherapy with the immune system, we studied the impact of chemotherapy in an aggressive mouse model of ovarian cancer developed within our lab. METHODS: Using a single-cell transcriptomics sequencing approach, supported by flow cytometry, we evaluated the influence of a first-line therapy, cisplatin and docetaxel, and a second-line therapy, pegylated liposomal doxorubicin (PLD), on control of tumor growth and on tumor-associated immune populations of cells. RESULTS: Both chemotherapy approaches were effective at controlling tumor growth and selectively depleted tumor cells from distinct transcriptional clusters. Both chemotherapies also resulted in relative increases in immune populations compared to untreated tumor-bearing mice, but immune populations from PLD-treated mice were more abundant and expressed a greater fraction of maturity-associated transcripts and increased proportions of tumor resident macrophage populations. PLD treatment selectively upregulated MHC class II on tumor cells, and this could be replicated in vitro across ovarian cancer cell lines and in patient tumor cells ex vivo. CONCLUSIONS: Altogether, the results support the notion that PLD has a greater capacity for immunopotentiation, which may be important to consider if immunotherapy approaches are adapted for ovarian tumors in the future.

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