Nature Cancer: LCOR mRNA therapy combined with PD-L1 inhibitor successfully challenges triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for 12%-20% of all breast cancers and is characterized by negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).

Immune checkpoint inhibitors represented by PD-1/PD-L1 antibodies can release the body's anti- tumor immune response and play an anti-cancer effect

Source: Nature Cancer

 A team from the Hospital del Mar Medical Research Institute found that in triple-negative breast cancer (TNBC), cancer stem cells are able to evade the immune system, and that increased expression levels of a protein called LCOR (ligand-dependent corepressor) can interfere with this.

In triple negative breast cancer (TNBC), CSCs may account for 5%-50% of total tumors and can give rise to new tumors

Cancer stem cells (CSCs) lead to immune editing escape and immune checkpoint inhibitor (ICB) resistance (Source: Nature Cancer)

Breast cancer with low expression of LCOR has low activity of the antigen-presenting mechanism of CSC (Source: Nature Cancer)

LCOR promotes tumor immune infiltration and killing (Source: Nature Cancer)

To test this finding, the scientists applied anti-PD-L1 therapy in a triple-negative breast cancer (TNBC) mouse model

Preclinical and clinical significance of LCOR combined with ICB (Source: Nature Cancer)

In 5 independent experiments, the research team observed 49 complete responses (CR) in 50 LCOR-overexpressing tumors

Inspired by the COVID-19 mRNA vaccine, the team believes that expressing therapeutic proteins by delivering mRNA is a viable strategy, so they designed an mRNA therapy to restore LCOR expression in tumor cells

In mice, LCOR mRNA therapy (delivered by extracellular vesicles) in combination with a PD-L1 inhibitor overcomes tumor resistance, resulting in significantly longer survival in mice compared to PD-L1 inhibitor alone or control therapy prolonged and completely cleared lung metastases

Efficacy of EV-delivered Lcor mRNA therapy combined with ICB in the treatment of breast cancer metastasis

"Our experimental results demonstrate that an LCOR-based therapeutic strategy confers unprecedented sensitivity to immunotherapy in TNBC, resulting in near cure of this drug-resistant tumor
.
These positive results encourage us to move forward with clinical trials, and we will explore this whether this strategy can be applied to other tumors
," said Dr Joan Albanell, who co-led the study
.

It is reported that the Hospital del Mar Medical Research Institute has applied for a patent on the discovery (LCOR in combination with immunotherapy) and plans to create a spin-off company to further develop this anti-cancer mRNA therapy
.

Original source:

Iván Pérez-Núñez et al.
LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.
Nature Cancer(2022).