Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

Abstract

Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression.

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

“…There were no observable strain differences noted relating to guadecitabine treatment between the C57Bl/6 J and Balb/cJ mice. The tumor line E0771 is not known to elicit a robust leukemoid reaction, but studies still indicate a suppressive role for MDSCs in this model [41,42]. Overall, we observed a similar and persistent reduction in tumor growth with guadecitabine alone, or in combination with AIT.…”

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

“…Finally, we showed the effectiveness of guadecitabine in slowing the growth of another tumor line on a different background strain. Although E0771 is not known to elicit a robust leukemoid reaction, studies still indicate a suppressive role for MDSCs in this model (41,42). We observed a similar and persistent reduction in tumor growth with guadecitabine alone, or in combination with AIT.…”

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

“…Various pathological conditions, including cancer, can perturb myelopoiesis and interrupt IMC differentiation, resulting in accumulation of MDSCs (2, 4–9). In human cancer patients and mouse tumor models, massive accumulation of MDSCs is a hallmark of tumor progression (10–16). MDSCs are therefore key targets in cancer immunotherapy (1, 17–21).…”