THE IMPACT OF HISTAMINE RECEPTOR 2 ANTAGONISTS ON BREAST CANCER DEVELOPMENT AND MONOCYTIC POPULATIONS

Abstract

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer-related death. There is an urgent need for immunomodulatory drugs which specifically target immune cells to activate an antitumour response, or inhibit the immunosuppressive microenvironment induced by the tumour. Monocytes have been shown to be involved in many aspects of tumour development, including tumour growth, invasion, metastasis, and immunosuppression. One population of monocytes involved in immunosuppression are the monocytic myeloid-derived suppressor cells (M-MDSCs), an immature population of monocytic cells capable of suppressing an antitumour immune response and directly enhancing tumour development. Histamine is an immune mediator that has previously been studied in the context of cancer. Histamine can signal through four histamine receptors. Signaling through histamine receptor 2 (H2) is often immunosuppressive. We evaluated whether blockade of H2 signaling would alleviate this immunosuppression and therefore inhibit breast tumour development. We utilized two injectable orthotopic breast cancer models and one spontaneous breast cancer model. Our results showed that continuous oral treatment with the commonly used H2 antagonist ranitidine decreased tumour progression. The nature of this response differed between models, ranging from increased tumour latency to decreased metastasis. These effects were dependent on the presence of monocytes and/or M-MDSCs. Ranitidine did not impact tumour development when monocytes were depleted or their recruitment was inhibited. In one model, this process was found to be independent of CD8+ T cells. Ranitidine treatment led to decreased immune suppression and decreased monocyte numbers consistent with reduced monocyte development in the context of H2 blockade. Overall, our results indicate that ranitidine decreased MDSCs, thereby enhancing immunosurveillance, antitumour immunity, and subsequently decreasing tumour development. These findings indicate an urgent need for clinical studies to investigate the use of commonly used H2 antagonists in the prevention and treatment of breast cancer.