Since the first checkpoint inhibitor drugs were developed for the treatment of cancer over a decade ago, researchers have focused on ways to make them more effective. A study published on November 24 in the journal Cancer cell reports that second-generation over-the-counter antihistamines appear to improve outcomes for cancer patients treated with anti-PD-1 / PD-L1 therapies for a number of different cancer types.
“We believe that our results could have implications for clinical practice if validated in prospective clinical studies,” says lead author Dihua Yu, professor and acting chair of the Department of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center. “For example, our study suggests that before immunotherapy treatment, testing patients’ plasma histamine levels could help doctors decide whether patients may benefit from antihistamine treatment.”
The discovery was made after investigators decided to examine the influence of 40 common drugs on the effectiveness of checkpoint inhibitors. These included over the counter drugs such as antacids and anti-inflammatories and prescription drugs such as antibiotics and steroids. When researchers looked at electronic patient health records, they found that taking H1 antihistamines by patients receiving immunotherapy was significantly associated with improved overall survival.
Second generation H1 antihistamines include cetirizine (Zyrtec), loratadine (Claritin) and, more recently, fexofenadine (Allegra). These drugs, which block metabolites called histamines released by immune cells, are widely used in cancer patients not only to relieve allergy symptoms, but also to prevent nausea and vomiting. However, the role of histamines has not previously been linked directly to cancer outcomes.
Meanwhile, the researchers noticed that some patients with “hot tumors” – those with high infiltration of cytotoxic T cells – who would normally respond well to immunotherapy still had very poor survival. To gain insight into what made these tumors different, they performed a comprehensive gene expression analysis on patient samples.
“We found that histamine receptor 1 (HRH1) was identified as one of the main findings showing a strong association with poor clinical outcomes in hot tumors,” says co-lead author Yi Xiao, instructor from the Department of Molecular and Cellular Oncology and a member of Yu’s lab at MD Anderson.
Since H1 antihistamines specifically block histamine binding to HRH1, they have linked the above results to the lab in mice. Their experiments revealed that the histamines released by cancer and allergic reactions, as well as the high expression of HRH1 in macrophages, suppressed the activation of cytotoxic T cells and conferred resistance to immunotherapy, while antihistamines have partially saved all phenotypes.
They also measured plasma histamine levels before treatment in patients treated with anti-PD-1 immunotherapy. Corroborating their findings in mice, elevated histamine levels in patients were significantly correlated with lower responses to anti-PD-1 immunotherapy compared to patients with low plasma histamine levels.
“We were surprised to find that almost all of the cancer cells we tested had dramatically increased histamine secretion compared to normal cells,” Xiao said. “We know that allergic responses release a lot of histamines, but we didn’t expect such a surprising suppressive effect on anti-tumor immunity.”
One of the limitations of the research is that it has focused only on the function of HRH1 expressed by macrophages, but not on HRH1 in other immune and non-immune cell types. The researchers say it’s also possible that histamines have a broader impact on the phenotype and activity of macrophages. It’s something they could explore in the future.
They also note that choosing the right antihistamines for cancer patients is essential. This research indicated that only second generation H1 antihistamines, which specifically target HRH1, but not first generation non-selective H1 antihistamines, led to better results.
“Tens of millions of people suffer from allergies every year. But the impact of allergies on cancer development and therapeutic response has not been well studied, ”said Yu.“ Our study has just uncovered a tip of the iceberg, and we will continue to explore the relationship between both diseases. “
This work was primarily supported by the National Institutes of Health and METAVivor.
Cancer cell, Li and Xiao et al. : “Histamine, a mediator of allergy, confers resistance to immunotherapy in cancer patients via the activation of histamine receptor 1 in macrophages” https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00602-4
Cancer cell (@Cancer_Cell), published by Cell Press, is a monthly journal that provides a high-level forum to promote major advances in cancer and oncology research. The review covers topics related to molecular and cellular mechanisms of cancer, mechanisms of sensitivity and resistance to cancer therapies, development of better cancer therapies and clinical investigations. Visit: http://www.cell.com/cancer-cell. To receive Cell Press media alerts, contact [email protected]
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Histamine, a mediator of allergy, confers resistance to immunotherapy in cancer patients by activating the histamine receptor 1 of macrophages.
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