Lack of histamine H4 receptor in tumor microenvironment results in reduced agressiveness in a model of breast cancer. role of antitumor immunity.

HELENA STERLE; DIEGO J MARTINEL LAMAS; MELISA N NICOUD; MARIA V HERRERO DUCLOUX; VANINA A MEDINA; NOELIA A MASSARI; GRACIELA CREMASCHI

Congreso; European Histamine Research Society 46th Annual Meeting. 11 al 13 de Mayo de 2017. Amsterdam, Holanda; 2017

The expression of histamine H4 receptors (H4R) as well as histamine-induced modulation of proliferation in different types of tumors has previously been reported. However, the role of H4R in the tumor microenvironment, including in immune cells, had not yet been studied. Our present work aimed to investigate the effect of the lack of H4R in the tumor microenvironment on breast cancer development and progression. We evaluated growth parameters, histological characteristics of tumors and the composition of tumoral immune subsets in a syngeneic model of breast cancer developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild-type (WT) mice. Mice lacking H4R showed reduced tumor size and weight and exhibited a more differentiated histopathological pattern (grade 2) compared with WT mice (grade 3, highly aggressive potential). Tumors of H4R-KO mice displayed a significant decrease in neutrophils (number of neutrophils per field: 3.2±0.9 vs. 9.0±2.1, P˂0.05) while non-significant differences in angiogenesis were observed. The lack of H4R was associated with an increase in the percentage of CD8+ (32.0±2.5 vs. 16.1±3.1, P˂0.05) and CD19+ (27.2±4.8 vs. 6.5±1.5, P˂0.01) tumor-infiltrating lymphocytes and a decrease in CD4+ lymphocytes (11.9±3.4 vs. 19.4±1.2, P˂0.05). Similar differences in immune subsets were observed in the spleen. Finally, H4R-deficient mice showed non-significant changes in lung metastasis. These results suggest an interplay between H4R-expressing cells in the tumor microenvironment and cancer cells, which has implications for breast cancer progression.