ANTITUMORAL AND IMMUNOMODULATORY ROLE OF HISTAMINE IN BREAST CANCER

MELISA NICOUD; HELENA STERLE; NOELIA MASSARI; MONICA TAQUEZ DELGADO; KARINA FORMOSO; VERONICA HERRERO DUCLOUX; DIEGO MARTINEL LAMAS; VANINA MEDINA

Mar del Plata

Congreso; Reunion Anual de la Sociedad Argentina de Investigación Clínica; 2018

Sociedad Argentina de Investigación Clínica

It is well known that histamine is a key regulator of immune cell functions and it also modulates cancer cell proliferation. The aim of this work was to investigate the effect of histamine and its H4 receptor (H4R) agonist (JNJ28610244) on tumor growth and in the immune tumor microenvironment as a whole, in a triple negative breast cancer syngeneic model developed in immunocompetent mice. Tumors of the TNBC cell line 4T1 were established in Balb/c mice. Treatments employed: histamine (1 or 5 mg/kg) and JNJ28610244 (1 or 5 mg/kg). Results show that histamine treatment (5 mg/kg) reduces tumor growth more effectively than JNJ28610244. Histamine but not the agonist increases tumor apoptosis and it reduces the number of intratumoral vessels. Histamine also reduces immunosuppression through the modulation of the tumor microenvironment, as it increases the tumor secretion of IFN gamma and reduces the number of T regulatory (Treg) lymphocytes in lymph nodes and Spleen.A lower concentration (1 mg/kg) of JNJ28610244 reduces tumor size while no immunomodulatory effects are observed in the immune cell subsets studied. In contrast, a higher concentration (5 mg/kg) is not able to decrease tumor growth probably because of the immunosuppressive effect produced in the tumor microenvironment, showing increased levels of interleukin (IL)-10 and decreased levels of IFN gamma in tumors and increased infiltrating Treg cells in tumor draining lymph nodes. These results highlight the critical interplay between tumor cells and host immune response that determine the clinical therapeutic outcomes and suggest that histamine is a key pleiotropic mediator with therapeutic benefits in TNBC.