Faculty, Staff and Student Publications
Publication Date
1-10-2022
Journal
Cancer Cell
Abstract
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.
Keywords
Cell Line, Tumor, Histamine, Humans, Immune Tolerance, Immunotherapy, Macrophages, Neoplasms, Receptors, Histamine, Tumor Microenvironment
DOI
10.1016/j.ccell.2021.11.002
PMID
34822775
PMCID
PMC8779329
PubMedCentral® Posted Date
1-10-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Graphical Abstract
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Medical Cell Biology Commons, Oncology Commons
