Mouse CD45+ immune cells data at single-cell resolution

To further explore the impact of HRH1 blockade on macrophage phenotype and tumor immune microenvironment in vivo, single-cell RNA sequencing (scRNA-seq) was performed to analyze the CD45+ immune cells isolated from EO771 tumors growing in WT vs HRH1 KO mice. In retrospective screening of common medications that may affect immunotherapy response in patients, we found that patients who took antihistamines during immunotherapy treatment had significantly improved survival. Further study uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in tumor microenvironment to induce T-cell dysfunction. Mechanistically, HRH1 activation in macrophages polarizes them toward an M2-like immunosuppressive phenotype and increases membrane expression of immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) in macrophage, which renders CD8+ T-cells dysfunctional. Knockout HRH1 or antihistamine treatment negated the immunosuppressive activity of the macrophages, revitalized T-cell cytotoxic function, and restored immunotherapy response. Fascinatingly, both animal and human data showed that allergy facilitated tumor growth and induced immunotherapy resistance via histamine/HRH1 axis, underscoring the tumor-prone activity of allergy. More importantly, cancer patients with low levels of plasma histamine (0.6ng/ml). These findings demonstrate that pre-existing allergy or high levels of histamine in cancer patients can dampen response to immunotherapies and warrant perspective investigation of antihistamines as an adjuvant agent for combinatorial immunotherapy.