The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1
| Autor: | J. Jack Lee, Xuedong Yin, Cassian Yee, Wenling Kuo, Hongzhong Li, Yuan Zhang, Yi Xiao, Li Qin, Huihui Fan, Guosheng Ren, Don L. Gibbons, Hideo Yagita, Da Pang, Yohei Saito, Dihua Yu, Ping Li, Jun Yao, Angela Halpin, Zhongming Zhao, Xiangliang Yuan |
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| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Allergy medicine.medical_treatment Histamine Antagonists Article Histamine receptor chemistry.chemical_compound Cancer immunotherapy Cell Line Tumor Neoplasms Immune Tolerance Tumor Microenvironment Humans Medicine Tumor microenvironment business.industry Macrophages Immunotherapy medicine.disease Immune checkpoint Oncology chemistry Immunology Receptors Histamine Antihistamine business Histamine |
| Zdroj: | Cancer Cell |
| ISSN: | 1535-6108 |
| Popis: | Summary Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy. |
| Databáze: | OpenAIRE |
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