Study uncovers new role for histamine receptor,
suggesting possible treatment approach in combination with checkpoint
inhibitors
MD Anderson News Release November 24, 2021
New research from The University of Texas MD
Anderson Cancer Center found that treatment with antihistamines, a
commonly used allergy medication, was associated with improved responses to
immune checkpoint inhibitors. The preclinical study demonstrated that the
histamine receptor H1 (HRH1) acts in tumor-associated macrophages (TAMs) to suppress
T cell activation in the tumor microenvironment. The findings were published
today in Cancer Cell.
If replicated in prospective clinical trials, the data
suggest that targeting HRH1 may be useful as a treatment approach in
combination with checkpoint blockade to overcome immunotherapy resistance and
improve outcomes, particularly for patients 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, Ph.D., 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.”
Antihistamines associated with improved
immunotherapy outcomes
Immune checkpoint inhibitors, a type of immunotherapy, work by blocking certain
checkpoint proteins that regulate the activity of T cells, unleashing the T
cells to mount an anti-tumor response and eliminate cancer cells. Checkpoint
blockade provides long-lasting responses for many patients, but not all benefit
equally. Therefore, there is a desire to better understand factors that
contribute to immunotherapy sensitivity or resistance.
This study began with the researchers investigating if
other commonly used medications might influence responses to checkpoint
inhibitors. They performed a retrospective analysis of clinical data from MD
Anderson patients undergoing treatment with immune checkpoint inhibitors.
In those 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.
Using The Cancer Genome Atlas and other publicly
available patient cancer data, the team also 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.
Histamine receptor acts in tumor
microenvironment to suppress T cell activation
Following the correlations observed, the researchers
sought to clarify the possible contributions of HRH1 and its ligand, histamine,
to the immune response.
They discovered both proteins were elevated in the tumor
microenvironment, but 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 in the tumor microenvironment, known as M2-like macrophages, that
contribute to immune suppression. Conversely, cancer cells appear to be a major
source of increased histamine levels in patient samples and cancer cell lines.
In preclinical models, 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.
To understand how HRH1 in TAMs influences T cell
activity, the researchers looked at additional regulatory receptors on the
macrophages. Blocking HRH1 activity reduced the membrane localization of VISTA,
an inhibitory receptor known to suppress T cell activation. Further, blocking
HRH1 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 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 anti-tumor response.
Targeting HRH1 enhances checkpoint blockade
responses in preclinical models
In preclinical models of breast cancer and melanoma,
combining an antihistamine with checkpoint blockade enhanced therapeutic
efficacy and prolonged survival over checkpoint blockade alone. Additionally,
the antihistamine achieved similar responses in preclinical models as treatment
with anti-VISTA antibodies, which are currently being evaluated in clinical
trials.
Further, the researchers used a preclinical model of
allergic disease to investigate the effects on tumor progression. After
allergies were induced, histamine levels and tumor growth increased relative to
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 anti-tumor response.
“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,” said corresponding author Dihua Yu, M.D., Ph.D., chair ad
interim of Molecular & Cellular Oncology. “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.”
Moving forward, the team is working to design
prospective clinical trials to evaluate the combination of antihistamines and
checkpoint inhibitors in patients with cancer.
This research was supported by the National Institutes
of Health (R01CA112567, R01CA184836, R01CA208213, and P30CA016672), the Cancer
Prevention & Research Institute of Texas (CPRIT) (RP180734) and grants from
METAvivor.
A full list of collaborating authors can be found with
the full paper here. The authors have no conflicts of
interest.
No comments:
Post a Comment