Studies headed by scientists at the University of Texas MD Anderson Cancer Center suggest that an over-the-counter, second-generation antihistamine drug could improve outcomes for cancer patients who are treated using anti-PD-1/PD-L1 checkpoint inhibitors for a number of different types of cancer. The researchers made their discovery when looking at the influence of dozens of common medications on the efficacy of checkpoint inhibitors. A review of patient data showed that for some tumor types, taking H1-antihistamines in addition to receiving immunotherapy was significantly associated with improved overall survival. A preclinical study in rodents demonstrated that the histamine receptor H1 (HRH1) acts in tumor-associated macrophages (TAMs) to suppress T-cell activation in the tumor microenvironment.
If replicated in clinical trials, the findings could point to targeting HRH1, in combination with checkpoint blockade, as an approach to overcoming immunotherapy resistance and improving patient outcomes, particularly for those with pre-existing allergies or high plasma histamine levels. “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 study co-lead Yi Xiao, PhD, instructor of molecular & cellular oncology. “Looking closer at this relationship, we discovered that histamine, through its receptor HRH1, can promote cancer cell immune evasion and resistance to immunotherapy.”
Added co-senior author Dihua Yu, MD, PhD, professor and chair ad interim of the department of molecular and cellular oncology at the University of Texas MD Anderson Cancer Center, “We believe our findings could have implications for clinical practice if validated in prospective clinical studies. For example, our study suggests that before immunotherapy treatment, testing patients’ plasma histamine level could help doctors decide whether patients may benefit from antihistamine treatment.”
Xiao, Yu, and colleagues reported on their findings in Cancer Cell, in a paper titled, “The allergy mediator histamine confers immunotherapy resistance in cancer patients via activation of the macrophage histamine receptor 1,” in which they concluded, “… 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.”
T cell-mediated immunity plays a key role in the host’s defense against cancer, but cancer cells can co-evolve with the tumor immune microenvironment, and develop strategies to evade T cell immune attack and destruction, the authors noted. As such, “reinvigoration” of antitumor immunity remains an unmet challenge. Immune checkpoint inhibitors are a type of immunotherapy that work by blocking certain checkpoint proteins that regulate the activity of T cells, unleashing the T cells to mount an antitumor response and eliminate cancer cells. Checkpoint blockade provides long-lasting responses for many patients, but not all patients will benefit. “Anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, as immune checkpoint blockade (ICB) therapies, have yielded significant clinical benefits and durable responses in a subset of cancer patients,” the authors noted. “Yet, many cancer patients cannot benefit from these treatments, and it is highly challenging to reach immunotherapy’s full potential.” Scientists, therefore, want to better understand factors that might contribute to immunotherapy sensitivity or resistance.
To try and gain some insight into what might impact cancer patients’ responses to immunotherapy, the team looked at the influence of 40 common medications on the efficacy of checkpoint inhibitors, by performing a retrospective analysis of clinical data from MD Anderson patients undergoing treatment with immune checkpoint inhibitors. The medications they considered included over-the-counter drugs such as antacids and anti-inflammatories, and prescription drugs such as antibiotics and steroids.
Their review of patients’ electronic health records indicated that among immunotherapy-treated patients with melanoma or lung cancer, concurrent use of antihistamines targeting HRH1 was correlated with significantly improved survival outcomes. Patients with breast or colon cancer also displayed similar trends, although the data did not reach statistical significance due to a relatively small sample size.
“Surprisingly, we found that antihistamines are associated with significantly improved clinical outcome, and antihistamines may achieve this via reinforcing antitumor immunity, raising an interesting question: how do antihistamines, which block histamine binding to histamine receptors, influence antitumor immunity?” the investigators wrote.
Second-generation H1-antihistamines include cetirizine (Zyrtec), loratadine (Claritin), and, more recently, fexofenadine (Allegra). These drugs, which block 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 connected directly to cancer outcomes. “Generally, the roles of histamine and histamine receptors in cancer development are unclear,” the authors pointed out. In fact, prior studies focused on histamine receptor expression on cancer cells have led to “controversial” findings that HRHs may either promote or inhibit cancer growth, the investigators commented. Furthermore, they noted, “… allergic reactions release a lot of histamine and affect tens of millions of people every year, yet the potential impacts of allergy on cancer and cancer therapies have not been investigated.”
Using the Cancer Genome Atlas and other publicly available patient cancer data, the team then discovered that high expression of HRH1 in tumors was correlated with markers of T cell dysfunction, poor responses to checkpoint inhibitors, and poorer survival outcomes. Seeking to clarify the possible contributions of HRH1 and its ligand, histamine, to the immune response, the investigators discovered that both proteins were elevated in the tumor microenvironment, but that they did not appear to come from the same source. HRH1 was not present in cancer cells but was highly expressed in certain types of TAMs—known as M2-like macrophages—in the tumor microenvironment, which contribute to immune suppression. Conversely, cancer cells appeared to be a major source of increased histamine levels in patient samples and cancer cell lines.
Further studies in preclinical models showed that blocking HRH1 on macrophages—either by genetic knockout or antihistamine treatment—decreased the immune-suppressive activity of the TAMs, leading to increased T-cell activation and inhibition of tumor growth. Looking to understand how HRH1 in TAMs influences T cell activity, the researchers evaluated additional regulatory receptors on the macrophages. They found that blocking HRH1 activity reduced the membrane localization of VISTA, an inhibitory receptor known to suppress T cell activation. Further, blocking HRH1 also caused broad changes in gene expression, resulting in a shift from M2-like features to a more pro-inflammatory state consistent with M1-like macrophages. The collective mechanistic data demonstrated that HRH1 acts in TAMs to drive cells toward an immune-suppressive M2-like state and to increase membrane expression of the inhibitory checkpoint VISTA, ultimately leading to dysfunctional T cells and a suppressed antitumor response.
Further experiments in preclinical models of breast cancer and melanoma showed that combining an antihistamine with checkpoint blockade enhanced therapeutic efficacy and prolonged survival, when compared with checkpoint blockade alone. Interestingly, the antihistamine achieved similar responses in preclinical models as did treatment with anti-VISTA antibodies, which are currently being evaluated in clinical trials.
The researchers used a preclinical model of allergic disease to investigate the effects on tumor progression. They found that after allergies were induced, histamine levels and tumor growth increased, relative to the controls. However, these effects could be reversed with antihistamine treatment. Similarly, the researchers demonstrated a correlation between plasma histamine levels in patients with cancer and responses to immune checkpoint inhibitors. These findings suggest that elevated histamine levels, either from allergies or cancer cell production, may contribute to suppression of the antitumor response. “We were surprised to find that almost all the cancer cells we tested have significantly increased secretion of histamines compared to normal cells,” Xiao said. “We know that allergy responses release a lot of histamines but didn’t expect such a stunning suppressive effect on antitumor immunity.”
Corresponding author Yu also noted, “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. 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 … Tens of millions of people experience allergies every year. But how allergies impact cancer development and therapeutic response has not been well studied. Our study just uncovered a tip of the iceberg, and we will continue to explore the relationship between the two diseases.”
One limitation of the research is that it focused solely on the function of macrophage-expressed HRH1 but not HRH1 in other immune and non-immune cell types. The researchers say it’s also possible that histamines may have a broader impact on the phenotype and activity of macrophages. This is something that they may explore in the future. They also noted that it would be critical to choose the right antihistamines for cancer patients. Their reported research indicated that only second-generation H1-antihistamines, which target HRH1 specifically, but not first-generation, non-selective H1-antihistamines, led to improved outcomes.
Moving forward, the team is working to design prospective clinical trials to evaluate the combination of antihistamines and checkpoint inhibitors in patients with cancer.