Immunotherapy aims to turn the body’s immune system into an ally in the fight against cancer. One way that can happen is by stimulating T cells to identify and kill unwanted tumor cells. Unfortunately, it’s not successful in every patient, as tumors can become resistant to the T cells’ attacks. The mechanisms behind this resistance are varied, and new ones continue to be uncovered. But the secret to overcoming some of them might already be in medicine cabinets everywhere: antihistamines.
A paper published today (November 24) in Cancer Cell reports that high levels of histamine—best known for being released in response to allergens—and one of its receptors are associated with tumor resistance to immunotherapy drugs called immune checkpoint inhibitors in patients with a range of cancer types. In tumor cells, immune checkpoints are proteins expressed to evade surveillance; by inhibiting them, checkpoint therapy boosts antitumor defenses. The study also shows that patients who happened to be taking antihistamine treatment responded better to immune checkpoint inhibitor therapy than those not on antihistamines. Using tumor cells and mouse models, the authors further uncovered details on the mechanism behind this effect.
“It sounds really exciting that antihistamines may be beneficial in a subset of patients undergoing immunotherapy,” says University of South Australia immunologist Damon Tumes, who did not participate in the study. “It’s just a matter of proving that with controlled trials.”
Becca Martin, an immunologist at the Virginia Commonwealth University who also was not involved in the research, agrees that if this intervention can be combined with immunotherapy to improve the patients’ outcome, it could be a really important addition. “Antihistamines are cheap drugs that have been around for a long time.”
The goal is to make more patients benefit from immunotherapy, says Dihua Yu, a cancer researcher at MD Anderson in Texas and corresponding author of the new study. Her team first approached this quest by looking at whether common drugs consumed in combination with immune checkpoint inhibitors may influence the patients’ response to this cancer treatment. By retrospectively scanning data of patients receiving immunotherapy together with any of 40 common drugs—antibiotics, aspirin, and hydrocortisone, among them—they found that melanoma and lung cancer patients taking antihistamines that target the histamine receptor H1 (HRH1), such as fexofenadine, loratadine, and cetirizine, had significantly higher survival rates.
This initial result, showing “you have an increased survival in checkpoint therapy if you are [taking] antihistamines” is one of “the most impressive” within the paper, according to Martin.
Based on this first promising hint at the beneficial role of antihistamines, Yu and her team explored the role that histamine and its receptor might play in the immune response to cancer. In existing patient samples, they found that high levels of HRH1 in tumors were correlated with markers of T cell dysfunction and poor survival in patients suffering from certain cancer types. These histamine receptors were mainly expressed in tumor-associated macrophages, a class of immune cells often involved in suppressing the anti-tumor response.
In follow-up experiments in mice, the binding of histamine to HRH1 receptors on the surface of tumor-associated macrophages contributes to the suppression of T cell function, resulting in tumor resistance to immunotherapy. Specifically, blocking the histamine receptors on macrophages—either through gene knockouts or treatment with the antihistamine fexofenadine—restored T cell antitumor activity, ultimately inhibiting tumor growth in the animals.
“This is a sophisticated, detailed, exhaustive, and original study that provides new insights into combinatorial therapeutic approaches targeting H1 receptors to improve cancer immunotherapy,” Vanina Medina, a biomedical researcher at the Pontifical Catholic University of Argentina who was not involved in the study, writes in an email to The Scientist.
Tumes says the evidence presented for the role of histamine in tumor response to immunotherapy is strong. “The question for me is where the histamine is coming from,” he says.
Yu and her colleagues found that both histamine and HRH1 are upregulated in the tumor microenvironment, suggesting that cancer cells are one of the major sources of increased histamine levels in cancer patients. But the authors of the study also explored histamine released from allergic reactions. Based on an allergic disease mouse model and on clinical data from patients reporting allergic reactions before undergoing immunotherapy, they conclude that histamine released from an allergy response also affects response to checkpoint inhibitors.
Tumes says that, in his opinion, the evidence for this link between allergy and response to immunotherapy is not as robust. Moreover, previous controversial data on the link between allergies and cancer begs for further research on this question, he says. In summary, these new findings just indicate that “in some contexts, histamine from allergy might be important for immune evasion by the tumor, and more work needs to be done to . . . confirm or refute that hypothesis.”
MD Anderson cancer researcher and study coauthor Yi Xiao says these new findings provide “strong evidence” of the benefits of combining antihistamine treatment with immunotherapy, but still a “prospective clinical trial to prove it” is needed. While the team does not yet have “a solid plan” to perform such a study, Yu says, there is excitement among the physicians collaborating with them to start one.