Antihistamines Associated With Improved Immunotherapy Response in Patients With Cancer

Treatment with antihistamines was associated with improved responses to immune checkpoint inhibitors, according to a study published in Cancer Cell. The investigators demonstrated that the histamine receptor H1 (HRH1) acts in tumor-associated macrophages (TAMs) to suppress T cell activation in the tumor microenvironment.

“In searching for factors that might influence responses to immunotherapy, we were surprised to discover that antihistamines, a mediator of the allergy response, were associated with significantly improved outcomes in patients,” said Yi Xiao, PhD, in a press release. “Looking closer at this relationship, we discovered that histamine, through its receptor HRH1, can promote cancer cell immune evasion and resistance to immunotherapy.”

The investigators performed a retrospective analysis to determine whether commonly used medications might influence responses to checkpoint inhibitors. In patients with melanoma or lung cancer, concurrent use of antihistamines targeting HRH1 was correlated with significantly improved survival outcomes.

Similar trends were observed in patients with breast or colon cancer, though the relatively small sample size meant that these data did not reach statistical significance. If the results from this preclinical study can be replicated in prospective clinical trials, HRH1 may be a useful treatment target in combination with checkpoint blockade to overcome immunotherapy resistance and improve patient outcomes.

Investigating the source of this correlation, the investigators found that HRH1 and histamine were both elevated in the tumor microenvironment but did not appear to share the same source. HRH1 was not present in cancer cells but was highly expressed in certain types of TAMs in the tumor microenvironment that contribute to immune suppression.

Conversely, cancer cells appear to be a major source of increased histamine levels in patient samples and cancer cell lines, according to the investigators.

“Our preclinical findings suggest that antihistamines have the potential to enhance responses to immunotherapy, especially in those with high levels of histamine in the blood,” said Dihua Yu, MD, PhD, in the release. “There is more work to be done, but we are excited to continue exploring possible therapeutic applications with antihistamines, which offer an inexpensive approach with minimal side effects.”

The investigators are currently developing prospective clinical trials to evaluate the combination of antihistamines and checkpoint inhibitors in patients with cancer.

REFERENCE

Antihistamines can influence immunotherapy response by enhancing T cell activation [news release]. EurekAlert; November 24, 2021. Accessed November 30, 2021. https://www.eurekalert.org/news-releases/935552