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. 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 inhibits proinflammatory signaling, dysregulates fatty acid metabolism, 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. 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.