A new study from the University of Texas MD Anderson Cancer Center suggests that antihistamines, a popular allergy drug, can boost responses to immune checkpoint inhibitors.
The preclinical study found that the histamine receptor H1 (HRH1) suppresses T cell activation in the tumor microenvironment in tumor-associated macrophages (TAMs).
The results of the study were published today in Cancer Cell.
The findings imply that targeting HRH1 in combination with checkpoint blockade may be effective in overcoming immunotherapy resistance and improving outcomes, especially in patients with pre-existing allergies or high plasma histamine levels.
“We were surprised to discover that antihistamines, a mediator of the allergy response, were associated with significantly improved outcomes in patients,” says study co-lead Yi Xiao. “Looking closer at this relationship, we discovered that histamine, through its receptor HRH1, can promote cancer cell immune evasion and resistance to immunotherapy.”
Antihistamines linked to improved immunotherapy outcomes
Immune checkpoint inhibitors are a form of immunotherapy that works by blocking particular checkpoint proteins that control T cell function, allowing T cells to develop an anti-tumor response and kill cancer cells. Many patients benefit from checkpoint blocking, however not all patients benefit equally. As a result, there is a desire to learn more about the factors that influence immunotherapy sensitivity or resistance.
The researchers wanted to see if other regularly used drugs influenced responses to checkpoint inhibitors, so they started with that. They conducted a retrospective study of clinical data from MD Anderson patients who were receiving immune checkpoint inhibitor medication.
Concurrent use of antihistamines targeting HRH1 was linked to dramatically improved survival outcomes in people with melanoma or lung cancer. Similar trends were seen in patients with breast or colon cancer, albeit the findings did not achieve statistical significance due to the limited sample size.
The study also discovered that elevated HRH1 expression in tumors was linked to markers of T cell dysfunction, poor responses to checkpoint inhibitors, and lower survival outcomes, using data from The Cancer Genome Atlas and other publically available patient cancer data.
Histamine receptor inhibits T cell activation in the tumor microenvironment.
The researchers wanted to know if HRH1 and its ligand, histamine, play a role in the immune response based on the connections they found.
They discovered that both proteins were enhanced in the tumor microenvironment, but that they did not appear to be derived from the same source as they had previously thought. M2-like macrophages are a form of TAM found in the tumor microenvironment that contribute to immune suppression. HRH1 was not found in cancer cells, but it was shown to be significantly expressed in certain types of TAMs in the tumor microenvironment. Cancer cells, on the other hand, appear to be a primary source of elevated histamine levels in both patient samples and cancer cell lines, according to research.
In preclinical studies, inhibiting HRH1 on macrophages — either through genetic knockout or antihistamine administration – lowered the immune-suppressive function of TAMs, resulting in enhanced T cell activation and tumor growth inhibition.
Additional regulatory receptors on macrophages were investigated to further understand how HRH1 in TAMs affects T cell activation, according to the research team. Reduced membrane localization of VISTA, an inhibitory receptor known to prevent T cell activation, was seen following the inhibition of HRH1 activity. Moreover, the inhibition of HRH1 induced extensive gene expression alterations that resulted in a shift away from M2-like characteristics and toward a more pro-inflammatory state comparable with M1-like macrophages.
It was determined from the mechanistic findings that HRH1 operates in TAMs to push cells into an immune-suppressive M2-like state and to boost membrane expression of the inhibitory checkpoint VISTA, ultimately resulting in malfunctioning T cells and a suppressed anti-tumor response to the tumor.
In preclinical models, targeting HRH1 improves the effectiveness of checkpoint blockage.
An antihistamine used in conjunction with immune checkpoint inhibition was found to improve therapeutic efficacy and prolong survival in preclinical models of breast cancer and melanoma when compared to checkpoint inhibitors used alone. The antihistamine also produced results in preclinical animals that were comparable to those obtained by therapy with anti-VISTA antibodies, which are currently being studied in human trials.
The researchers also employed a preclinical model of allergic sickness to explore the impact of the drug on the course of tumor growth. Histamine levels rose when allergies were created, and tumor growth increased in comparison to control groups. Antihistamine therapy, on the other hand, has the potential to reverse these effects.
Similarly, the researchers discovered a link between plasma histamine levels and immune checkpoint inhibitor responses in cancer patients. These data imply that increased histamine levels, whether caused by allergies or cancer cell development, may play a role in the anti-tumor response being suppressed.
“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,” says corresponding author Dihua Yu.
“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.”
Source: 10.1016/j.ccell.2021.11.002
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