Allergic mediator histamine confers immunotherapy resistance in cancer patients via histamine receptor 1 on macrophage

How to revive anti-tumor immunity in cancer patients is an unmet challenge. Retrospective screening of common medications revealed that patients who took antihistamines during immunotherapy treatment had significantly improved survival. We further uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in tumor microenvironment to cause T-cell dysfunction. HRH1 activation in macrophages inhibits proinflammatory signaling and dysregulates fatty acid metabolism. HRH1 also increases membrane expression of immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) in macrophages, 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. Both animal and human data showed that allergy facilitated tumor growth and induced immunotherapy resistance via histamine/HRH1 axis, underscoring the tumor-p rone activity of allergy. These findings demonstrate that pre-existing allergy in cancer patients can dampen response to immunotherapies and warrant perspective investigation of antihistamines as an adjuvant agent for combinatorial immunotherapy. Overall design: We analyzed global gene expression profile of naïve macrophages derived from bone marrow of wild type C57BL/6 mice, tumor conditioned macrophages from wild type C57BL/6 mice and HRH1-/- C57BL/6 mice.