Histamine modulates tumor growth and antitumor immunity in 4T1 triple negative breast cancer developed in H4R knock-out (H4R KO) and wild-type (WT) BALB/c mice

STERLE H, ; PERAZZO JC, ; MARTINEL LAMAS D, ; MEDINA V. ; NICOUD M, ; CREMASCHI GA,

FLORENCIA

Congreso; 45th European Histamine Research Society (EHRS) Meeting; 2016

European Histamine Research Society (EHRS)

It is well-known that histamine regulates cellular immune responses, affecting maturation and activity of lymphocytes and myeloid-derived suppressor cells, which are considered as potential effectors of antitumor immunity and may interfere with tumor progression.The aim of the present work was to investigate the influence of the lack of histamine H4 receptor (H4R) on the tumorigenic capacity, metastatic potential and antitumor immunity in response to histamine in a triple negative breast cancer (TNBC) model. For that purpose, we evaluated tumor growth parameters, the phenotype of splenic and intra-tumoral lymphocytes in syngeneic H4R knock-out (H4R KO) and wild-type (WT) mice, inoculated orthotopically with 4T1 murine TNBC cells. CD4+, CD8+, CD11b+, C19+,CD3+, NK1.1+ cells were quantified in spleen and tumors by flow cytometry.Results indicate that histamine (0.1-10 µM) produced a 2-fold decrease in proliferation evaluated by BrdU-incorporation without inducing significant apoptosis in vitro in 4T1 TNBC cells. We observed non-significant differences in latency period or tumor growth between WT and KO mice while spleen weight was significantly higher in WT than in KO mice. Histamine subcutaneous administration (1 mg/kg.day) reduced tumor volume (743 vs. 1045 mm3 after 15 days of treatment, P˂0.05) and weight only in KO mice. Most of the animals showed lung metastases and non-significant differences were observed upon histamine treatment. However, histamine treatment reduced the intra-tumoral vascularization. In addition, CD11b+ immune cells were significantly reduced in spleen and tumor of KO mice compared with WT mice. Histamine further decreased CD11b+ cells while increased CD19+ cells in KO mice.In conclusion, the present study demonstrates that histamine regulates the growth of TNBC and the modulation of tumor immunity seems to be involved in histamine effects.