Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma.

The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes. The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells. Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD-L1 protein expression according to 5% and 1% PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1% cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001). PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma.

Takada K ，Okamoto T ，Shoji F ，Shimokawa M ，Akamine T ，Takamori S ，Katsura M ，Suzuki Y ，Fujishita T ，Toyokawa G ，Morodomi Y ，Okano S ，Oda Y ，Maehara Y ... -  《-》

Programmed Cell Death Ligand 1 Expression in Resected Lung Adenocarcinomas: Association with Immune Microenvironment.

Programmed cell death ligand 1 (PD-L1) expression on tumor cells can be upregulated via activation of CD8+ cytotoxic T lymphocytes (CTLs) or the T helper cell (Th1) pathway, counterbalancing the CTL/Th1 microenvironment. However, PD-L1 expression in association with subtypes of tumor-associated lymphocytes and molecular alterations has not been well characterized in lung adenocarcinomas. PD-L1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and various scoring systems, and was correlated with clinicopathologic/molecular features, including the extent/subtype of tumor-associated lymphocytes (i.e., CD8, T-bet [Th1 transcription factor], and GATA3 [Th2 transcription factor]), and patient outcomes. PD-L1 expression was present in 129 (49%), 95 (36.5%), and 62 (24%) cases using cutoffs of ≥1%, ≥5%, and ≥50%, respectively, 98 (38%) by H score and 72 (28%) by immune score. PD-L1 expression was associated with abundant CD8+ and/or T-bet+ tumor-infiltrating lymphocytes and EGFR wild-type, significant smoking history, and aggressive pathologic features. In addition, concurrent PD-L1 expression and abundant CD8+ tumor-associated lymphocytes were seen in 25% of KRAS mutants or cases with no alterations by clinical molecular testing as opposed to only 7.4% of EGFR mutants. PD-L1 expression was significantly associated with decreased progression-free and overall survival rates by univariate analysis, but not by multivariate analysis. PD-L1 expression in resected lung adenocarcinomas is frequently observed in the presence of CTL/Th1 microenvironment, in particular in those with KRAS mutations or no common molecular alterations, suggesting that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute active immune response for at least a subset of such patient populations.

Huynh TG ，Morales-Oyarvide V ，Campo MJ ，Gainor JF ，Bozkurtlar E ，Uruga H ，Zhao L ，Gomez-Caraballo M ，Hata AN ，Mark EJ ，Lanuti M ，Engelman JA ，Mino-Kenudson M ... -  《-》

Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status.

PD-L1 expression is a predictive biomarker for response to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors and can be evaluated by immunohistochemistry. Results of the clinicopathologic characteristics of PD-L1-positive lung adenocarcinoma have been inconsistent in previous studies, and there are no reports on the relationship between PD-L1 expression and p53 status in lung adenocarcinoma. We examined PD-L1 and p53 expression in a total of 323 surgically resected lung adenocarcinoma cases using anti-PD-L1 (clone SP142) and anti-p53 (clone DO-7) antibodies, and analyzed the clinicopathologic characteristics of PD-L1-positive cases and their relationship with p53 status. PD-L1 expression in tumor cells was positive in 60 of 323 cases (18.6%). Higher PD-L1 expression (≥50%) was more prevalent in former or current smokers (p=0.026) and was associated with more pack-years (p=0.016). PD-L1-positive tumors were significantly associated with solid predominant type (p<0.001), p53 aberrant expression (p<0.001), and PD-L1 expression in tumor-infiltrating immune cells (p<0.001). Patients with stage I to III tumors harboring PD-L1-positive tumor cells showed poor recurrence-free survival (p<0.001) and overall survival (p<0.001) on univariate analysis. PD-L1 expression in tumor cells, solid predominant histology, p53 aberrant expression, and PD-L1 expression in tumor-infiltrating immune cells are closely related. These variables should be considered when analyzing the clinical outcomes of patients with lung adenocarcinomas treated with anti-PD1/PD-L1 immune checkpoint inhibitors.

Cha YJ ，Kim HR ，Lee CY ，Cho BC ，Shim HS ... -  《-》

Programmed death-ligand 1 expression associated with molecular characteristics in surgically resected lung adenocarcinoma.

Song Z ，Yu X ，Cheng G ，Zhang Y ... -  《Journal of Translational Medicine》

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma.

Wu S ，Shi X ，Sun J ，Liu Y ，Luo Y ，Liang Z ，Wang J ，Zeng X ... -  《Oncotarget》