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Review
. 2021 Sep 20;9(5):1181-1193.
doi: 10.1016/j.gendis.2021.08.009. eCollection 2022 Sep.

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

Xiaoxin Ren  1 , Yixian Li  2 , Christopher Nishimura  1 , Xingxing Zang  1   3   4
Affiliations
Review

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

Xiaoxin Ren et al. Genes Dis. .

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.

Keywords: Combination therapies; EGFR; Immune checkpoint blockade; New B7/CD28 members; PD-1/PD-L1 pathway.

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Figures

Figure 1
Figure 1
Schematic overview of crosstalk between the EGFR signaling and the B7/CD28 family. Pathways known to be involved in the EGFR-mediated signaling are depicted. Activation of EGFR by either ligand interaction or activating gene alteration leads to downstream signaling pathways that ultimately drive tumor proliferation, survival and induce pro-tumoral cytokines. EGFR signaling activation induces PD-L1 upregulation by activation of the PI3K/AKT, RAS/RAF/MEK/ERK or JAK/STAT3 pathways. These pathways involved in the EGFR signaling also mediate B7-H3 signaling, however, the crosstalk between these two pathways remains to be determined. B7x and HHLA2 are also associated with activating EGFR mutations through unclear mechanisms. IL-6 and IL-10 induced by EGFR activation may induce B7x expression in macrophages through JAK/STAT3 signaling, which represents a potential mechanism by which EGFR upregulates B7x expression. The upregulation of HHLA2 could result in the inhibition of T and NK cell response through interacting with its inhibitory receptor KIR3DL3. JAK, Janus kinase; NF-κB, nuclear factor kappa B; PI3K, phosphatidylinositol-4,5-Bisphosphate 3-kinase; PLC, phospholipase C; PD-1, programmed cell death protein-1; PD-Ll, programmed death ligand-1; STAT3, signal transducer and activator of transcription 3; HHLA2, human endogenous retrovirus-H long terminal repeat-associating protein 2; KIR3DL3, killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3; NK cell, natural killer cell; B7x, B7 homolog x.
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