Abstract
BackgroundAlthough the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer.MethodsWe evaluated growth parameters, histological characteristics and the composition of tumour, splenic and tumour draining lymph node (TDLN) immune subsets, in a syngeneic model, developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild-type mice.ResultsMice lacking H4R show reduced tumour size and weight, decreased number of lung metastases and percentage of CD4+ tumour-infiltrating T cells, while exhibiting increased infiltration of NK cells and CD19+ lymphocytes. Likewise, TDLN of H4R-KO mice show decreased CD4+ T cells and T regulatory cells (CD4+CD25+FoxP3+), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4+, CD19+ and NK splenic cells, suggesting that H4R also regulates antitumour immunity at a systemic level.ConclusionsThis is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment.
Highlights
Cancer is a major public health issue, representing one of the main causes of death in the world
H4 receptor (H4R)-KO mice exhibit reduced tumour growth and metastasis In agreement with previous studies in human breast cancer cell lines,[24,25] the expression of H4R in 4T1 cells was demonstrated by RT-PCR and immunostaining (Fig. 1a, b)
Consistent with these results, tumours developed in H4R knockout (H4R-KO) mice showed increased apoptosis and decreased vascularisation along with a reduced number and size of lung micrometastasis compared to tumours of WT animals (Fig. 2d, g, h, j)
Summary
Cancer is a major public health issue, representing one of the main causes of death in the world. A large body of data revealed the importance of the leukocyte infiltrate in controlling the clinical progression of various types of epithelial cancers.[3] Cells of immune system are key constituents of the tumour microenvironment and may promote or inhibit the development and progression of cancer.[4] One of the common features of most tumour processes is the inflammation that can contribute to proliferation and survival of malignant cells, promote angiogenesis and metastasis, altering the responses to hormones and chemotherapeutic agents.[2] On the other hand, the immune system through tumour immune surveillance, is responsible for the removal of nascent tumour cells, preventing tumour progression and formation of micrometastases.[2,5] There are immunosuppressive mediators in the tumour microenvironment that regulate the activity and efficiency of cells with antitumour capacity, controlling the elimination of tumour cells In this regard, immunotherapy has emerged as a useful therapeutic approach for the treatment of many cancers as it stimulates the immune system to detect and eradicate tumour cells. H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4+, CD19+ and NK splenic cells, suggesting that H4R regulates antitumour immunity at a systemic level. CONCLUSIONS: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment
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