Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities

Xiaoxin Ren, Yixian Li, Christopher Nishimura, Xingxing Zang

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1181-1193
Number of pages13
JournalGenes and Diseases
Issue number5
StatePublished - Sep 2022


  • Combination therapies
  • EGFR
  • Immune checkpoint blockade
  • New B7/CD28 members
  • PD-1/PD-L1 pathway

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics(clinical)
  • Cell Biology


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