Estrogen Receptor ‘Hijack’ Explains Immunotherapy Resistance in Moast Common Breast Cancer
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A groundbreaking study reveals why luminal breast cancer, the most prevalent form of the disease, often fails to respond to immunotherapy. Researchers at the Hospital del Mar Research Institute in Barcelona discovered that a high expression of the estrogen receptor actively suppresses the immune system’s ability to recognize and attack tumor cells.
The research,published in The journal of Clinical inquiry on Thursday,details how the estrogen receptor interferes with the function of a molecule called LCOR,which is crucial for signaling the immune system to target cancerous cells. Essentially,the estrogen receptor “kidnaps” LCOR,preventing it from making tumors visible to immune defenses.
The Challenge of Treating Luminal Breast Cancer
Approximately 70% of all breast cancer diagnoses are classified as luminal breast cancer. Despite the availability of effective treatments,this subtype remains the leading cause of breast cancer-related deaths. Currently, immunotherapy is largely ineffective against luminal tumors, except in a small percentage of patients with low estrogen receptor levels.
“This study explains a basic reason why immunotherapy has struggled to gain traction in the majority of breast cancer patients,” a senior official stated.
Unlocking the Immune System’s Potential
In experimental models, the research team demonstrated that combining immunotherapy with endocrine therapy – treatments that target estrogen receptors – can restore LCOR function and enable the immune system to attack the tumor. This suggests a potential pathway to overcome the resistance observed in many patients.
Researchers found that inhibiting the estrogen receptor allows for the activation of both LCOR and interferon signals, both of which are vital for presenting tumor antigens on the cell surface, effectively flagging the cancer cells for immune destruction.
A ‘Kidnapped’ Molecule and a Modified Solution
The team created a preclinical model to confirm that the estrogen receptor actively prevents LCOR from performing its immune-boosting role – a role it effectively plays in other types of breast cancer. To circumvent this “kidnapping” effect, researchers experimented with a modified version of the LCOR molecule, dubbed LSKAA.
This Modified LCOR is designed to evade the estrogen receptor’s grasp and enhance antigen presentation, thereby triggering a robust immune response. The team also combined LCOR and immunotherapy with existing hormone inhibitors or endocrine therapy.
New Hope for Immunotherapy in Breast Cancer
John Albanell, head of the Medical Oncology Service at Hospital del Mar and director of the center’s Cancer Research Program, believes the study opens the door to a “new strategy” for sensitizing this dominant breast cancer subtype to immunotherapy.
“The objective is to work to convert this Modified LCOR into a therapy that can be investigated soon in clinical trials, especially for patients with tumors with estrogen receptors that currently condition a poor efficiency of immunotherapy,” Albanell explained.
This research represents a significant step forward in understanding the complex interplay between hormones, the immune system, and breast cancer, o
