Recently, researchers from the Hospital del Mar Medical Research Institute in Spain published a research paper entitled: LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer in Nature Cancer.
The study found that cancer stem cells in triple-negative breast tumors had low expression of ligand-dependent corepressor (LCOR), which led to their escape from immunotherapy. On this basis, the research team used LCOR mRNA in combination with PD-L1 inhibitors to completely eliminate triple-negative breast cancer cells in a mouse model and prevent cancer recurrence, achieving a complete cure.
Although triple-negative breast cancer accounts for only 15% of all breast cancers, it is the most advanced breast cancer subtype and affects young patients significantly.
Cancer Stem Cells are cells in tumors with self-renewal ability and can generate heterogeneous tumor cells, which play an important role in the survival, proliferation, metastasis and recurrence of cancer cells.
When using immunotherapy such as immune checkpoint inhibitors, cancer stem cells are able to evade immunotherapy, leading to evasion and resistance to immunotherapy. What is the mechanism behind this?
In this study, the research team found that cancer stem cells in triple-negative breast cancer have low expression of ligand-dependent corepressor (LCOR), leading to "invisible" to them by the immune system and resulting in poor clinical response to immunotherapy in triple negative breast cancer.
The research team further found that activating the expression of the LCOR gene in a mouse model reversed the immune escape of cancer stem cells and resensitized them to immunotherapy.
The research team validated it in clinical samples from triple-negative breast cancer patients and found that patients who responded to immune checkpoint inhibitors had higher levels of LCOR gene expression.
Image: LCOR pre versus post ICB
Inspired by the COVID-19 mRNA vaccine, the research team wants to deliver the mRNA of the LCOR gene into tumor cells in a similar way, so that the immune system can re-recognize it.
The research team used LCOR mRNA delivered by extracellular vesicles in combination with PD-L1 inhibitors to treat a mouse model of triple-negative breast cancer. The results showed that 49 of the 50 treated mice experienced a complete remission, the only one that did not respond was because of loss of ectopic expression of LCOR. All 49 mice in complete remission were free of tumor recurrence 2 months after drug withdrawal.
The research team further followed up 15 of the mice for up to 1 year. None of the mice had tumor recurrence, while the lifespan of laboratory mice was only 1-3 years, which shows that this combination therapy can eradicate and completely cure the tumors in these mice.
In general speaking, this study found and demonstrated an important role for the LCOR gene in regulating tumor immunogenicity and cancer cell response to tumor immunotherapy. In triple-negative breast cancer, the expression level of LCOR in cancer stem cells correlates with the clinical efficacy of immune checkpoint inhibitors. The study further demonstrates that LCOR mRNA delivery via extracellular vesicles (EVs) in combination with PD-L1 inhibitors can overcome drug resistance in triple-negative breast cancer and eradicate cancer cells and prevent cancer recurrence in preclinical models. These data support the LCOR gene as a promising target for boosting immune checkpoint blockade therapy in triple-negative breast cancer.
It is reported that the research team has applied for a technology patent for the combined use of LCOR mRNA and immunotherapy, and will create a company to transform this technology patent and promote its clinical application.
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