Targeting histamine H4 receptor improves anti-tumoral response in a murine model of breast cancer

Breast cancer is one of the most common malignant tumors in women worldwide. Histamine (HIS) has been associated with either pro-tumor or anti-tumor effects, depending on the receptor evaluated. It exerts its physiological and pharmacological functions through four receptors (H1R-H4R). In breast cancer, it promotes tumor growth by activating H1 and H2 receptors. Furthermore, HIS released into the tumor microenvironment can promote inflammation associated with tumor development and immunosuppression of the immune response. Several years ago, breast cancer was shown to express the H4R, although conflicting data exist; its activation is associated with tumor progression and the development of metastases.

In this study, using a murine model of breast cancer with the 4T1 cell line, we investigated in depth the role of H4R in tumor progression. We demonstrated that H4R blockade with the specific antagonist JNJ777120 (JNJ) inhibits tumor cell line proliferation, migratory capacity, and ROS production, while increasing lactate release and rapidly and transiently ERK kinase activation. In vivo, the antitumorigenic effect of JNJ appears to depend on the adaptive immune response, as suggested by the rapid recruitment of CD8⁺ cells, the increased lymphocyte proliferation from JNJ-treated tumors, and the absence of activity in the adaptive immune-deficient Rag1 mice. Moreover, tumor-derived cells showed altered energy metabolism.

Taken together, our results demonstrate the dual role of HIS via the H4R in 4T1 cells, modulating not only tumor cell development but also the immune microenvironment.