PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements

Yoneshima, Yasuto; Ijichi, Kayo; Anai, Satoshi; Ota, Keiichi; Otsubo, Kenji; Iwama, Eiji; Tanaka, Kentaro; Oda, Yoshinao; Nakanishi, Yoichi; Okamoto, Isamu

doi:10.1016/j.lungcan.2018.01.024

“…Progression‐free survival was significantly shorter in patients with high PD‐L1 expression than in those with low PD‐L1 expression. High PD‐L1 expression had been reported by several recent studies to correlate with shorter PFS after EGFR‐TKI treatment in EGFR ‐mutated NSCLC . The results of our study were similar to those of the previous reports, in terms of this point.…”

Section: Discussionsupporting

confidence: 92%

“…10,11,32 However, several recent reports showed that a relatively high PD-L1 expression in EGFR-mutated NSCLC was associated with worse response and PFS, even to EGFR-TKI. 18 likely to benefit less from EGFR-TKI therapies.…”

Section: Discussionmentioning

confidence: 99%

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Matsumoto

¹

,

Sawa

²

,

Fukui

³

et al. 2019

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We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8+ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

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“…These statistical analysis results showed significant correlations among EGFR mutants, p‐IκBα, HIF‐1α, and PD‐L1 protein levels in NSCLC tissues. In contrast, some other retrospective studies have reported that PD‐L1 positivity was more frequent in NSCLC tissues carrying WT EGFR and other studies have shown no association between PD‐L1 expression and EGFR mutations . The discrepancies among these studies might be caused by the heterogeneous study population and variable definitions of PD‐L1 expression.…”

Section: Discussionmentioning

confidence: 87%

“…In contrast, some other retrospective studies have reported that PD-L1 positivity was more frequent in NSCLC tissues carrying WT EGFR and other studies have shown no association between PD-L1 expression and EGFR mutations. [51][52][53] The discrepancies among these studies might be caused by the heterogeneous study population and variable definitions of PD-L1 expression. Additionally, our present findings indicated the necessity to explore the effects of genetic and environmental factors on NF-κB and HIF-1α in the studying of PD-L1 expression regulation by EGFR mutants.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

¹

,

Li

²

,

Wang

³

et al. 2019

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Some driver gene mutations, including epidermal growth factor receptor ( EGFR ), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 ( PD ‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD ‐L1 expression regulation in non‐small‐cell lung cancer ( NSCLC ) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD ‐L1 overexpression and phosphorylation of AKT and ERK , especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD ‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR . Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK / ERK , PI 3K/ AKT , mTOR /S6, IκBα, and HIF ‐1α indicated strong accordance among protein levels of PD ‐L1, p‐IκBα, and HIF ‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF ‐1α, and PD ‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF ‐1α, and PD ‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR . Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF ‐1α positive staining were more likely to possess elevated PD ‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF ‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF ‐κB and HIF ‐1α in PD ‐L1 expression regulation by EGFR mutants in NSCLC .

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“…Several studies have revealed that the level of PD‐L1 expression is significantly higher in patients with ALK fusion or EGFR mutation, and these driver oncogenic alterations induce PD‐L1 expression by activating downstream signaling pathways in NSCLC . However, other studies have shown conflicting results . Therefore, precise analysis of PD‐L1 expression and correlations with oncogenic driver mutations and smoking is still worthwhile.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of ≥ 50% PD‐L1 expression with the SP263 monoclonal antibody in non‐small cell lung cancer patients

Li

¹

,

Song

²

,

Guo

³

et al. 2018

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Background PD‐L1 expression in tumor cells has been associated with the efficacy of immune checkpoint inhibitors in non‐small cell lung cancer (NSCLC). The aim of this study was to explore correlations between smoking, genetic profiles, patient outcomes, and PD‐L1 expression in NSCLC. Methods PD‐L1 expression was evaluated in 241 surgically resected specimens by immunostaining and 50% was set as the cutoff value. Results Of the 241 tumors analyzed, a PD‐L1 tumor proportion score (TPS) of ≥ 50% was detected in 35 cases (14.5%) and a TPS of < 50% in 206 cases (85.5%). A PD‐L1 TPS ≥ 50% was significantly associated with smoking and EGFR wild‐type status ( P < 0.001 and P = 0.039, respectively). Detailed assessment of smoking variables showed that total smoking duration was a predictor of a PD‐L1 TPS ≥ 50% ( P = 0.001). Univariate and multivariate survival analyses revealed that patients with a PD‐L1 TPS ≥ 50% had poorer disease‐free and overall survival than those with a PD‐L1 TPS < 50% ( P = 0.001 and P < 0.001, respectively). Conclusion The incidence of a PD‐L1 TPS ≥ 50% was significantly higher in smoking and EGFR wild‐type NSCLC patients, particularly in long‐term smokers. A PD‐L1 TPS of ≥ 50% was an independent adverse prognostic factor for survival in patients with NSCLC.

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PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements

Cited by 85 publications

References 24 publications

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Clinical significance of ≥ 50% PD‐L1 expression with the SP263 monoclonal antibody in non‐small cell lung cancer patients

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