Therapy resistance remains a challenge with immune checkpoint inhibitors, and a new study proposes targeting ligand-dependent corepressor (LCOR) in addition to known immune targets to improve outcomes.
Immunotherapy has revolutionized the overall cancer treatment landscape in recent years, and one of the most effective immunotherapy therapy strategies has been immune checkpoint inhibition. Still, many patients do not respond to immune checkpoint inhibitors (ICIs) or develop resistance to them, including in triple-negative breast cancer (TNBC). A recent study points to ligand-dependent corepressor (LCOR) as a potential target to make immune checkpoint blockades more effective in TNBC.
TNBC is an aggressive form of breast cancer, and a subset of TNBC patients have shown promising responses with immunotherapy relative to other breast cancer subtypes. LCOR mediates normal and cancerous breast stem cell differentiation, and cancer stem cells (CSCs) determine the heterogeneity of cancer phenotypes, which may help determine potential response to immunotherapy within individual phenotypes. CSCs also drive therapy resistance, although they are not well understood in the context of immunotherapy.
The current study, published in Nature Cancer, provides evidence that LCOR is a master transcriptional activator of antigen processing/presentation machinery (APM), the reduction of which drives immune escape and resistance to immune checkpoint inhibitors in TNBC, according to the study.
“In the mammary gland, normal mammary stem cells (MaSCs) and CSCs are usually governed by differentiating cell fate determinants and stem cell transcription factors,” study authors wrote. “LCOR is a differentiation factor sensitizing these to IFN, which drives intrinsic tumor cell differentiation and reduced tumor growth. However, how LCOR intersects the IFN response has never been explored and may be critical to understanding cellular immunity.”
To better understand ICI resistance in breast cancer, study authors generated a preclinical murine model of anti-PD-L1 ICB resistance in vivo. Tumors that developed resistance to PD-L1 inhibition were harvested in cell culture and their resistance was again confirmed in vivo.
Transcriptomic analysis found that APM loss was among the most downregulated pathways in treatment-resistant tumors, unsurprisingly followed by loss of interferon (IFN) signaling. Stem cell signatures and CSC-like signatures associated with breast cancer aggressiveness were among pathways that were upregulated in the ICI-resistant tumors.
A breast cancer immune blockade resistance signature (IRS) using the top 300 IRS genes was generated to assess the clinical significance of the findings. It was applied to RNA sequencing data from the TONIC trial (NCT02499367), including 53 metastatic TNBC cases treated with a PD-1 inhibitor after preinduction therapy. In non-responders, the IRS was highly enriched, which validated the proposed clinical value.
In available MaSC transcriptomic profiles, fetal MaSCs also showed downregulated APM pathway genes. These preclinical findings were also validated by analysis of human cells and suggest that low-LCOR CSCs have a defective APM system — a significant immune-evasive characteristic of cells resistance to ICIs.
They found that LCOR regulated APM both with and without IFN signals, pointing to its significant role in antigen presentation. Further, results suggest that LCOR promotes immunogenicity as well as adaptive immune infiltration in TNBC.
Analysis of the TONIC trial showed that responders to treatment had higher levels of LCOR, as did data from another clinical trial, I-SPY2 (NCT01042379). “These findings demonstrate that LCOR levels are associated with response to ICB-containing combination therapy in TNBC,” study authors wrote.
Based on in vivo research of combination LCOR mRNA therapy in combination with anti-PD-L1 therapy in mice with lung metastases, this may be a potential avenue for progress.
Overall, the study suggests that breast CSCs with downregulated LCOR shut contribute to ICI resistance in TNBC. Study authors conclude, “Collectively, these data support LCOR as a promising target for enhancement of immune checkpoint blockade efficacy in TNBC, by boosting of tumor APM independently of IFN.”
Pérez-Núñez I, Rozalén C, Palomeque JÁ, et al. LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer. Nat Cancer. Published online March 17, 2022. doi:10.1038/s43018-022-00339-4