TNBC treatment breakthrough: mRNA therapy + PD-L1 inhibitor greatly enhances the efficacy of immunotherapy

Article source: Medicine Cube Pro

Author: Man

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

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)

By studying PD-L1 immunotherapy-resistant tumors from mice, the scientists found that cancer stem cells that express low levels of LCOR have reduced antigen processing and presentation mechanisms

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

The study then found that in laboratory studies, LCOR-overexpressing TNBC tumor cells increased T cell activation, as more T cells entered the tumor and played a killing role

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

Further, the scientists also studied some tumor samples from TNBC patients who participated in clinical trials of different PD-1/L1 inhibitors, including Tecentriq, Opdivo and Imfinzi

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

Taken together, the scientists believe these data support LCOR as a promising target for improving the effectiveness of checkpoint inhibitors in TNBC

Note: The original text has been deleted

References:

[1] Iván Pérez-Núñez et al.

[2] An mRNA therapy improves breast cancer response to immunotherapy in mice (Source: FierceBiotech)

[3] Radical increase in the effectiveness of breast cancer immunotherapy (Source: Hospital del MarMedical Research Institute)