Tag: Mood and emotional regulation

New research led by investigators at Northwestern University has shown that an FDA-approved medication for asthma could be used to help improve the efficacy of immunotherapy against a range of hard-to-treat cancers. The research, published in Nature Cancer, shows that a pathway best known for its role in asthma and allergic inflammation may also help aggressive cancers evade immune attack by exploiting the inflammatory receptor CysLTR1 to reshape white blood cells into immune-suppressing cells that interfere with cancer immunotherapy. Blocking that pathway with existing drugs such as montelukast slowed tumor growth, restored immune activity and improved responses to anti-PD-1 immunotherapy in several mouse cancer models.

“When we turned off this switch, either genetically or with existing drugs, we not only slowed tumor growth, but also helped the immune system recover its ability to fight the cancer,” said senior author Bin Zhang, MD, PhD, a professor of cancer immunology at Northwestern University Feinberg School of Medicine.

CysLTR1, or cysteinyl leukotriene receptor 1, is a receptor activated by inflammatory lipid molecules called cysteinyl leukotrienes. Under normal conditions, the pathway helps regulate inflammatory responses associated with asthma, allergic rhinitis, and other inflammatory diseases and conditions. But in some cancer, the Northwestern researchers noted, this pathway is co-opted to promote what is called “emergency myelopoiesis,” during which bone marrow rapidly produces myeloid immune cells as a result of chronic inflammations. In cancer, this results in the generation of neutrophils and another class of tumor suppressors called PMN-MDSCs, which hinders immune activation against tumors.

“The ‘emergency’ myelopoiesis usually occurs to facilitate malignancy progression,” the researchers wrote. “Immunosuppressive neutrophils, also deemed as PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells), are potent mediators of immunosuppression and tumor promotion.”

The investigators reported that tumors activate inflammatory cytokines including GM-CSF and IL-6, which stimulate the STAT3 signaling pathway. STAT3 then increases expression of the CysLTR1 receptor. Once activated, CysLTR1 triggers AKT and ERK signaling pathways that promote neutrophil maturation, granule synthesis, and immune-suppressive activity.

The study showed that this pathway interferes with immunotherapy by limiting the ability of CD8-positive T cells to infiltrate tumors and kill cancer cells. Instead, the tumors accumulate suppressive neutrophils that block immune responses and contribute to resistance to immune checkpoint inhibitors such as anti-PD-1 therapy.

The research builds on prior studies showing that MDSCs and inflammatory neutrophils contribute to cancer progression and resistance to therapy. Earlier studies had documented expansion of suppressive myeloid cells in tumors, but the molecular programs controlling neutrophil differentiation and granule production were not known. The Northwestern researchers sought to identify the signaling pathways that connect tumor inflammation to immune suppression.

For their work, the team turned to mouse tumor models, human immune cells, tumor tissue samples, as well as analyses of public cancer datasets. The mouse studies included models of triple-negative breast cancer, melanoma, ovarian cancer, colon cancer, and prostate cancer. Against this variety of models, the researchers either genetically deleted CysLTR1 or inhibited it with drugs already used clinically for asthma and allergies, including montelukast, also known as Singulair.

The data showed that blocking CysLTR1 consistently reduced tumor growth and improved survival overall survival. In several models, tumors that had stopped responding to immunotherapy regained sensitivity to anti-PD-1 treatment after CysLTR1 inhibition.

The study also found that blocking the pathway did not just eliminate neutrophils, it also it altered how neutrophils behaved. “Importantly, instead of simply removing these harmful white blood cells, we were able to reprogram them into cells that support immune attack,” Zhang said. “That means we’re not just targeting the cancer, we’re re-training one type of abundant immune cells in the body to fight the tumor again.”

Mechanistically, the researchers found that CysLTR1 regulates transcription factors known as MXD1 and NFE2, which control genes involved in neutrophil granule production.

The team’s analysis of treatment data showed that patients with higher CysLTR1 expression had poorer survival and showed weaker responses to immune checkpoint blockade across multiple cancer types. The effectiveness of using montelukast in their studies as a means to inhibit CysLTR1, suggests that it could be used to help improve the efficacy checkpoint inhibitors against a range hard-to-treat cancers such as triple-negative breast cancer.

“We may be able to quickly and safely test it in cancer patients to improve immunotherapy. Especially in aggressive cancers, like triple-negative breast cancer, where new options are urgently needed,” Zhang said.

Because montelukast and related CysLTR1 antagonists are already approved by the FDA, and has a known safety profile, the drug could be moved rapidly into late-stage clinical testing. Future work would look to validate the treatment mechanism in patients, while also identifying which cancers and patient populations would most benefit from the use of this class of drug in combination with immunotherapy.

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