B7-H4 is increased in lung adenocarcinoma harboring EGFR-activating mutations and contributes to immunosuppression

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immunotherapy targeting PD-1/PD-L1 has shown efficacy in lung adenocarcinoma (LUAD).
• However, LUAD patients with EGFR-activating mutations (EGFR MT) exhibit reduced response to these therapies.
• This reduced response is linked to low PD-L1 expression, absence of tumor-infiltrating lymphocytes (TILs), and altered immune checkpoint molecule profiles.

Purpose of the Study:

• To investigate the differential expression of immune checkpoint molecules in LUAD subtypes with various driver mutations.
• To explore the association between B7-CD28 family members and EGFR mutations.
• To identify potential alternative therapeutic targets for LUAD with EGFR MT.

Main Methods:

• Dataset analysis of CD8A, GZMB, and PRF1 mRNA levels in LUAD subtypes.
• Investigation of the association between 15 B7-CD28 family members and driver mutations.
• Immunohistochemical staining for PD-L1 and B7-H4.
• In vitro studies in lung cancer cell lines examining pathway activation (MEK/ERK, PI3K/Akt).
• In vivo studies involving B7-H4 knockdown.

Main Results:

• EGFR MT-LUAD showed decreased CD8+ TILs, PD-L1, and CD86, with increased B7-H4 and HHLA2.
• PD-L1 expression correlated positively with CD8A and granzyme B, while B7-H4 correlated negatively with granzyme B.
• EGFR mutations upregulated B7-H4 and downregulated PD-L1 in cell lines.
• B7-H4 knockdown reversed EGFR mutation-induced CD8+ T-cell inhibition, suppressed tumor growth, and improved survival in vivo.

Conclusions:

• B7-H4 is upregulated and PD-L1 is downregulated in LUAD with EGFR MT, contributing to T-cell dysfunction.
• B7-H4 represents a potential alternative immune checkpoint and therapeutic target for this patient subset.
• Targeting B7-H4 may overcome resistance to current immunotherapies in EGFR MT-LUAD.