Exploring new strategy for breast cancer immunoprevention by targeting histamine receptor H1

New strategies to prevent breast cancer are urgently needed because: i) breast cancer incidence rates keep rising by 0.5% per year and about 13%, or 1 in 8, of U.S. women are going to develop invasive breast cancer in their life time; ii) the endocrine-targeted agents for ER+ breast cancer prevention do not reduce breast cancer mortality; iii) prevention strategy for ER- breast cancer, which has higher mortality rate, is still not available yet. Our recent study (published on Cancer Cell 2022 Jan 10;40(1):36-52) uncovered that high levels of plasma histamine and histamine receptor H1 (HRH1) expression in tumors (mainly on macrophages) are significantly correlated with reduced cytotoxic immune cell infiltration and devastating T cell function in patients with breast cancer. On the contrary, breast cancer patients who took H1-antihistamines during immunotherapy treatment had evidently improved survival. Importantly, the association between antihistamine uptake and better clinical outcome was only observed in patients treated with immunotherapies but not that with chemotherapies, suggesting that H1-antihistamines may contribute to antitumor immunity. Indeed, we found that H1-antihistamine treatment or HRH1 knockout boosted CD8+ cytotoxic T cell activities and enhanced immunotherapy responses in several mammary tumor models. More interestingly, our latest retrospective analysis of the electronic health record of a MDACC patient cohort with stage 0 or 1 breast cancers revealed that patients who took H1antihistamines had significantly reduced tumor recurrence compared to patients who did not take them. Patients who received therapies other than surgery were excluded, suggesting that the reduced recurrence is not due to enhanced therapeutic response. These new findings led us to hypothesize that blocking histamine-HRH1 axis by H1-antihstamines enhances immune surveillance and intercepts breast cancer development. We propose two Specific Aims: 1) Test the effect of H1-antihistamines on intercepting mouse mammary tumor development. We will test i) whether H1-antihistmaines can intercept early-stage mammary tumors in mouse models that mimic patients with early stage breast cancers (i.e., the cohort in the analysis); ii) whether H1-antihistamines will prevent/delay basal-like breast cancer initiation/progression in a genetically engineered mouse model which recapitulates the natural development of breast cancer; 2) Determine the impact of blocking histamine-HRH1 axis on systemic immune landscape and tumor immune microenvironment in early stage mammary tumors. We will examine i) broad effects of H1-antihistamine on blood immune cell landscape by CyTOF; ii) impacts of H1antihistamines on local immunity, e.g., the spatial interactions of mammary epithelial cells and diverse immune cell populations. Integrating above data, we will identify key changes of immune cells that are linked with antihistamine-mediated immunoprevention. The proposed study will explore a new strategy based on our latest findings to address the unmet challenge for breast cancer prevention. If the results are promising, our findings could be translated into clinic trials for immunoprevention of breast cancer, especially, in women at high-risk.