Breakthrough Strategy Overcomes Immunotherapy Resistance in Estrogen Receptor-Positive Breast Cancer
核心洞察
Researchers at Hospital del Mar Research Institute (搜索) have identified a mechanism to make immunotherapy (搜索) effective against estrogen receptor-positive breast cancer (搜索), which accounts for 70% of all breast cancer (搜索) cases.
The study reveals that estrogen receptors sequester the LCOR (搜索) molecule, preventing tumor cells from becoming visible to the immune system and blocking immunotherapy (搜索) effectiveness.
Scientists developed two strategies including a modified LCOR (搜索) version (LSKAA (搜索)) that escapes estrogen receptor (搜索) sequestration and enhances antigen presentation for immune attack.
Researchers at the Hospital del Mar Research Institute (搜索) have achieved a significant breakthrough in breast cancer (搜索) treatment by developing strategies to make immunotherapy (搜索) effective against estrogen receptor-positive breast cancer (搜索), the most common subtype that has historically shown resistance to immune-based therapies. The study, published in The Journal of Clinical Investigation, addresses a critical unmet need in treating the 70% of breast cancer cases classified as estrogen receptor (搜索)-positive or luminal breast cancer (搜索).
Despite effective existing treatments, estrogen receptor-positive breast cancer (搜索) causes the highest mortality in total cases due to its prevalence. Currently, immunotherapy (搜索) is not effective or approved for this subtype because it shows no immune system response in these tumors, except in a minority subgroup with low estrogen receptor (搜索) levels.
Estrogen Receptor's Role in Immune Evasion
The research team, led by Dr. Toni Celià-Terrassa from the Cancer Stem Cells and Metastasis Dynamics Laboratory, analyzed public data from various clinical trials to understand the mechanism behind immunotherapy (搜索) resistance. Their analysis revealed that the estrogen receptor (搜索) plays a crucial role in the tumor's strategy to evade immune system action by limiting immune system infiltration and preventing immunotherapy effectiveness.
"The estrogen receptor (搜索) sequesters LCOR (搜索) and prevents it from activating the antigen-presenting machinery, conditioning its function and not allowing the tumor to become 'visible'," explains Dr. Celià-Terrassa. The LCOR molecule, which has shown promise in increasing immunotherapy (搜索) effectiveness in triple-negative breast cancer (搜索) studies, becomes functionally inactive when sequestered by the estrogen receptor.
The researchers found that inhibiting the estrogen receptor (搜索) allows the activation of LCOR (搜索) and interferon signals, both factors related to antigen presentation mechanisms on the cell surface, making tumor cells visible to the immune system.
Preclinical Validation and Therapeutic Strategies
To confirm their findings, the research team generated preclinical models in animal studies, which validated the tumor protection mechanism. They then developed two distinct strategies to overcome estrogen receptor (搜索)-mediated immune evasion.
The first approach combines LCOR (搜索) and immunotherapy (搜索) with hormonal inhibitors, or endocrine therapy (搜索), already used to treat estrogen receptor-positive breast cancer (搜索). "Under normal conditions, estrogen signaling is prevalent in this type of tumor and prevents LCOR from acting. If we manage to break this signaling with antiestrogen therapy, LCOR activates antigen presentation and opens the path for immunotherapy," adds José Ángel Palomeque, researcher at the Hospital del Mar Research Institute (搜索).
The second strategy involves creating a modified version of LCOR (搜索) called LSKAA (搜索) that prevents sequestration by the estrogen receptor (搜索). This modified LCOR escapes the estrogen receptor's action and enhances antigen presentation, which is necessary for immune attack.
Translation to Clinical Applications
The RNA therapy generation laboratory at the Hospital del Mar Research Institute (搜索) is utilizing this technology to create modified LCOR (搜索) therapies that do not interact with the estrogen receptor (搜索) in combination with immunotherapy (搜索). The recently established spin-off company VIOLET Pharmaceuticals (搜索) focuses specifically on developing these types of therapies.
Dr. Joan Albanell, head of the Medical Oncology Service at the Hospital del Mar and director of the Cancer Research Program at the Hospital del Mar Research Institute (搜索), emphasizes the clinical significance of these findings. "This study opens the door to a new strategy to sensitize this subtype of breast cancer (搜索) to immunotherapy (搜索)," he states.
The research team's goal is to advance the modified LCOR (搜索) into a therapy that can be investigated in upcoming clinical trials, particularly for patients with tumors that present estrogen receptors, which currently limit the effectiveness of immunotherapy (搜索). This development represents a potential paradigm shift in treating the most common form of breast cancer (搜索), offering hope for improved outcomes in a patient population that has not benefited from the immunotherapy revolution in oncology.