New research from the University of Texas’ MD Anderson Cancer Center found that treatment with antihistamines, a commonly used allergy drug, was linked to improved responses to immune checkpoint inhibitors. The preclinical study showed that the histamine receptor H1 (HRH1) in tumor-associated macrophages (TAMs) acts to suppress T-cell activation in the tumor microenvironment. The results were published in Cancer Cell today.

When replicated in prospective clinical trials, the data suggest that targeted treatment for HRH1 in combination with checkpoint blockade could be useful in overcoming immunotherapy resistance and improving outcomes, especially in patients with pre-existing allergies or high levels Plasma histamine levels.

In searching for factors that might influence the response to immunotherapy, we were surprised to find that antihistamines, a mediator of the allergic reaction, were associated with significantly improved patient outcomes. Upon closer inspection of this relationship, we discovered that histamine, through its HRH1 receptor, can promote immune evasion of cancer cells and resistance to immunotherapy. “

Yi Xiao, Ph.D., Study Coordinator, Lecturer in Molecular and Cellular Oncology

Antihistamines in association with improved immunotherapy outcomes

Immune checkpoint inhibitors, a type of immunotherapy, work by blocking certain checkpoint proteins that regulate the activity of T cells, which T cells release to build an anti-tumor response and eliminate cancer cells. Checkpoint blockade provides long-lasting responses for many patients, but not all benefit equally. Hence, there is a desire to better understand factors that contribute to immunotherapy sensitivity or resistance.

That study began by investigating whether other commonly used drugs could affect the response to checkpoint inhibitors. They performed a retrospective analysis of clinical data from MD Anderson patients undergoing treatment with immune checkpoint inhibitors.

In patients with melanoma or lung cancer, the simultaneous use of antihistamines against HRH1 correlated with significantly improved survival results. Patients with breast or colon cancer also showed similar trends, although the data did not reach statistical significance due to a relatively small sample size.

Using the Cancer Genome Atlas and other publicly available cancer data from patients, the team also discovered that high levels of HRH1 expression in tumors correlated with markers of T-cell dysfunction, poor response to checkpoint inhibitors, and poorer survival outcomes.

Histamine receptor acts in the tumor microenvironment to suppress T cell activation

Following the correlations observed, the researchers tried to clarify the possible contributions of HRH1 and its ligand histamine to the immune response.

They discovered that both proteins were elevated in the tumor microenvironment, but they did not appear to be from the same source. HRH1 was not present in cancer cells but was strongly expressed in certain types of TAMs in the tumor microenvironment called M2-like macrophages, which contribute to immunosuppression. Conversely, cancer cells appear to be a major source of elevated levels of histamine in patient samples and cancer cell lines.

In preclinical models, HRH1 blocks macrophages -; either through genetic knockout or antihistamine treatment -; decreased the immunosuppressive activity of TAMs, which led to increased T-cell activation and inhibition of tumor growth.

To understand how HRH1 in TAMs affects T cell activity, the researchers examined additional regulatory receptors on the macrophages. Blocking HRH1 activity reduced the membrane localization of VISTA, an inhibitory receptor known to suppress T cell activation. Furthermore, blocking HRH1 resulted in profound changes in gene expression, resulting in a shift from M2-like traits to a more pro-inflammatory state consistent with M1-like macrophages.

The mechanistic data showed that HRH1 acts in TAMs to bring cells into an immunosuppressive M2-like state and to increase membrane expression of the inhibitory checkpoint VISTA, ultimately leading to dysfunctional T cells and a suppressed anti-tumor response.

Targeting HRH1 improves the checkpoint blockade response in preclinical models

In preclinical models of breast cancer and melanoma, combining an antihistamine with checkpoint blockade improved therapeutic efficacy and increased survival over checkpoint blockade alone. In addition, the antihistamine achieved a similar response in preclinical models as treatment with anti-VISTA antibodies, which are currently being evaluated in clinical studies.

In addition, the researchers used a preclinical model of an allergic disease to study the effects on tumor progression. After allergies were induced, histamine levels and tumor growth increased compared to controls. However, these effects could be reversed with antihistamine treatment.

Similarly, the researchers showed a correlation between plasma histamine levels in cancer patients and responses to immune checkpoint inhibitors. These results suggest that increased histamine levels, either due to allergies or the production of cancer cells, may contribute to suppressing the antitumor response.

“Our preclinical results suggest that antihistamines have the potential to improve response to immunotherapy, especially in patients with high blood histamine levels,” said corresponding author Dihua Yu, MD, Ph.D., ad interim chairman of Molecular & Cellular Oncology. “There is still much work to be done, but we look forward to continuing to explore potential therapeutic uses with antihistamines that offer a cost-effective approach with minimal side effects.”

In the future, the team is working on designing prospective clinical studies to evaluate the combination of antihistamines and checkpoint inhibitors in cancer patients.

Source:

University of Texas MD Anderson Cancer Center

Journal reference:

Li, H., et al. (2021) The allergy mediator histamine gives cancer patients resistance to immunotherapy by activating the macrophage histamine receptor H1. Cancer cell. doi.org/10.1016/j.ccell.2021.11.002.

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