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Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities
Xiaoxin Ren1, Yixian Li2, Christopher Nishimura1
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA.
Abstract:
Somatic activating mutations in the epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy, but patients inevitably experience acquired resistance. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types, their efficacy is limited in cancers harboring activating gene alterations of EGFR. Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3, B7x and HHLA2, is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment (TME). In this review, we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways. Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies. We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers, as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.
Insights
Activating mutations in the epidermal growth factor receptor (EGFR) drive many cancers. Combining EGFR-targeted therapies with immune checkpoint inhibitors may overcome resistance by modulating the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Somatic activating mutations in the epidermal growth factor receptor (EGFR) are key drivers in numerous cancers, including non-small-cell lung cancer.
- EGFR-targeted therapies are effective but often face acquired resistance.
- Immune checkpoint inhibitors (ICIs) show promise but have limited efficacy in EGFR-mutated cancers.
Purpose of the Study:
- To review the regulatory effects of EGFR signaling on PD-1/PD-L1 and novel B7/CD28 family pathways.
- To explore how EGFR signaling influences the tumor microenvironment and contributes to therapeutic resistance.
- To inform combination therapeutic strategies for overcoming resistance in EGFR-mutated cancers.
Main Methods:
- Literature review of studies on EGFR signaling, immune evasion, and therapeutic resistance.
- Analysis of the role of B7/CD28 family members (B7-H3, B7x, HHLA2) in EGFR-mutated cancers.
- Summary of clinical data for anti-PD-1/PD-L1 therapies and ongoing combination trials.
Main Results:
- EGFR signaling upregulates B7/CD28 family members, creating an immunosuppressive tumor microenvironment.
- This upregulation is associated with resistance to both EGFR-targeted therapies and current immunotherapies.
- Clinical data and ongoing trials are exploring combinations to enhance anti-tumor responses.
Conclusions:
- Understanding the interplay between EGFR signaling and immune pathways is crucial for developing effective cancer treatments.
- Combination strategies involving EGFR-targeted agents and ICIs hold potential to overcome therapeutic resistance.
- Further research and clinical trials are needed to optimize these combination therapies for EGFR-mutated cancers.
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