H1 antihistamines were associated with improved clinical outcome of immunotherapy treatments.
Major Finding: H1 antihistamines were associated with improved clinical outcome of immunotherapy treatments.
Concept: Histamine receptor H1 increases the cell membrane expression of the T-cell inhibitory receptor VISTA.
Impact: H1 antihistamines may potentially be used as an adjuvant treatment to improve immunotherapy response.
Patient response to immune checkpoint blockade (ICB) remains variable. To investigate what may affect a patient's response to this type of therapy, Li, Xiao, and colleagues conducted a retrospective analysis on the effect of the top 40 charted pharmaceutical drugs patients were taking while on ICB therapy and their influence on ICB response. The only drug found to be significantly correlated with better survival, outside of aspirin, which is known to reduce the immunotherapy death rate in mice, were antihistamines specific for histamine receptor H1 (HRH1). This was observed in patients with melanoma and lung cancer taking ICB treatments but was not observed in patients only on chemotherapy, indicating tumor cells were not being directly targeted. Further analysis revealed that high HRH1 expression correlated with the dysfunction of T cells as well as poor survival in triple-negative breast cancer (TNBC) and lung adenocarcinoma with a strong trend in melanoma. Additionally, tumors with high HRH1 expression demonstrated resistance to immunotherapy and had shorter overall survival. Investigation into the specific expression pattern of HRH1 revealed low expression on tumor cells but high expression on M2 immunosuppressive macrophages, with histamine, the ligand for HRH1, also being highly expressed in the blood of patients with TNBC and colon cancer. Antitumor immunity was restored upon HRH1 inhibition through polarization of macrophages back to an M1 phenotype and reduction of macrophage-mediated T-cell suppression. The effect of macrophage HRH1 on T-cell suppression was found to be mediated mostly by modulation of the inhibitory receptor, VISTA, expression on the cell membrane through alterations to Ca2+ release. Inhibition of HRH1 along with ICB treatment increased therapy response in multiple tumor models. Lastly, allergic responses led to significantly worse outcomes in both murine tumor models and retrospective patient analyses, and patients with high levels of plasma histamine had worse response to ICB compared to those with low levels of histamine. Thus, this study indicates the role that histamine or preexisting allergies play in ICB response and suggests the combinatorial use of H1 antihistamines to improve immunotherapy outcomes.
Li H, Xiao Y, Li Q, Yao J, Yuan X, Zhang Y, et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell 2022;40:36–52.e9.
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