Prof Liang Zhang published in Oncogene
Small molecular target EGFR inhibitor is the effective therapeutic strategy for clinical lung adenocarcinoma with EGFR activating mutations. However, emerging resistance limits the clinical benefit of the targeted therapy. PD-1/PD-L1 inhibitors have shown clinical benefits in lung adenocarcinoma (LUAD). However, the immunotherapy strategy is less effective in patients with EGFR-activating mutations (EGFR MT).
Recently, the group of Professor Liang Zhang published their research work in Oncogene. The paper titled “B7-H4 is increased in lung adenocarcinoma harboring EGFR-activating mutations and contributes to immunosuppression” reveals that B7-H4, another molecule of the B7 family, is upregulated whereas PD-L1 is downregulated in lung adenocarcinoma with EGFR activating mutations. MEK/ERK pathway activation increased B7-H4, while PI3K/Akt pathway activation increased PD-L1. Due to the cross-inhibition between MEK/ERK and PI3K/Akt pathways, the expression of B7-H4 and PD-L1 is negatively correlated. The upregulated B7-H4 means an alternative immune evasion pathway other than PD-L1 for lung adenocarcinoma with EGFR activating mutations. This study enlightens that B7-H4 is a potential immune therapeutic target for this subtype of Lung adenocarcinoma.
Professor Liang Zhang is the corresponding author, and Youwei Lu (Graduate of the School of Pharmaceutic science, Soochow University) and Fengying Wu ( Shanghai Pulmonary Hospital, Tongji University ) are the co-first authors.
In this paper, datasets GSE31210 and GSE75037 were analyzed. It showed that CD8+ infiltrated T cells, Granzyme B, and Perforin were decreased in EGFR mutant samples as compared with EGFR wild-type samples (Figure a). Among 15 co-stimulatory molecules, B7-H4 and HHLA2 were increased, and PD-L1 and CD86 were decreased in EGFR mutant samples (Figure b). Immunohistochemical staining of clinical samples verified the finding (Figure C). B7-H4 expression was negatively correlated with granzyme B, suggesting that B7-H4 could inhibit CD8+ T cells. All the results obtained from clinical samples indicate that in this subtype of lung cancer, B7-H4, not PD-L1, played an essential role in tumor immune evasion.
Many previous reports found that the expression of B7-H4 and PD-L1 are negatively correlated. In this study, transfected EGFR wild-type plasmid or mutant plasmids into lung cancer cells and found that EGFR mutant could activate MEK/ERK, thereby increasing B7-H4. However, EGFR mutant inhibited PI3K/Akt activation, thereby decreasing PD-L1 (Figure d). This finding explains the mechanism leading to the negative correlation between B7-H4 and PD-L1.
EGFR mutant could confer lung cancers with stronger CD8+ T cell inhibition, while blocking B7-H4 could reverse the inhibition, suggesting that B7-H4 is an important molecule involved in immune suppression (Figure e). A phase Ⅱ clinical trial revealed that B7-H4 expression is correlated with shorter overall survival in lung adenocarcinoma with EGFR activating mutations receiving anti -PD-1 therapy (Figure f). All the results suggest that B7-H4 is a potential immune therapeutic target.
Taken together, this study explains the exact immune evasion mechanism for lung adenocarcinoma with EGFR activating mutations and enlightens us that blocking B7-H4 might be an effective therapeutic strategy for this subtype of lung cancer.
Authors
Lu Y, Wu F, Cao Q, Sun Y, Huang M, Xiao J, Zhou B, Zhang L.
Oncogene. 2022 Jan;41(5):704-717. doi: 10.1038/s41388-021-02124-6.
1. The corresponding author
Liang Zhang, Professor, dean of the department of Biopharmaceutical
Major in tumor immunity
2. The first author
Youwei Lu, Master
Major in tumor immunity