Our results imply that EGFR-TKIs could not only directly inhibit tumor cell viability but also indirectly enhance antitumor immunity through the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for EGFR-TKI sensitive patients, especially for EGFR-TKIs resistant NSCLC patients with EGFR mutation. Combination of EGFR-TKIs and anti-PD-1/PD-L1 antibodies treatment in NSCLC is not supported by the current study but warrant more studies to move into clinical practice.

PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-κB pathways. Besides, IFN-γ was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.

BackgroundsRecent clinical trials have shown that immune-checkpoint blockade yields remarkable response in a subset of non–small cell lung cancer (NSCLC) patients. However, few studies directly focus on the association between epidermal growth factor receptor (EGFR) mutational status and programmed cell death-ligand 1 (PD-L1) expression. We examined whether PD-L1 is related to clinicopathologic factors and prognosis in patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs).MethodsOne-hundred and seventy patients with advanced NSCLC were explored. Paraffin-embedded tumour sections were stained with PD-L1 antibody. EGFR mutation was examined by fluorescent quantitative polymerase chain reaction (PCR). The correlations between PD-L1 expression and EGFR status and survival parameters were analyzed.ResultsThe overall frequency of PD-L1 over-expression was 65.9% (112/170). In lung adenocarcinoma, PD-L1 tended to be associated with mutant EGFR (PD-L1 overexpression in mutant and wild-type EGFR, 64/89 (71.9%) vs. 32/56 (57.1%), respectively; p=0.067). Subgroup analyses showed that high PD-L1 expression was associated with significantly shorter overall survival (OS) in EGFR wild-type patients (p=0.029) but not in EGFR mutant patients (p=0.932) treated with EGFR-TKIs. Even more, for EGFR mutant patients, higher expression of PD-L1 might only signal better outcome with TKIs.ConclusionsHigh PD-L1 expression was likely to be associated with the presence of EGFR mutation in advanced lung adenocarcinoma. For EGFR wild-type patients, the PD-L1 over expression can be considered as a poor prognostic indicator of OS.

Background:To verify whether the concentrations and integrity index of circulating cell-free DNA (ccf-DNA) in serum may be clinically useful for the diagnosis and progression monitoring of colorectal cancer (CRC) patients.Methods:Serum samples were collected from 104 with primary CRC, 85 with operated CRC, 16 with recurrent/metastatic CRC, 63 patients with intestinal polyps and 110 normal controls. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats (ALU-qPCR). Serum carcinoembryonic antigen (CEA) level was detected by ARCHITECT assay.Results:The median absolute serum ALU115 and ALU247/115 in primary CRC group was significantly higher than those in intestinal polyp and normal control groups (both P<0.0001), in recurrent/metastatic CRC was significantly higher compared with primary CRC (P=0.0021, P=0.0018) or operated CRC (P<0.0001, respectively) and during follow-up, ALU115 and ALU247/115 were increased before surgery and decreased significantly after surgery.Conclusions:Combined detection of ALU115, ALU247/115 and CEA could improve the diagnostic efficiency for CRC. Serum DNA concentrations and integrity index may be valuable in early complementary diagnosis and monitoring of progression and prognosis of CRC.

Recent studies have shown the prognostic nutritional index (PNI) had prognostic value in some solid tumors. However, no studies have examined its prognostic role in small-cell lung cancer (SCLC) patients. In this retrospective study, 724 consecutive SCLC patients were included between 2006 and 2013. Demographic, clinical, and laboratory data were collected. The PNI was calculated as 10 × serum albumin value (g/dl) +  .005 × peripheral lymphocyte count (per mm(3)). Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. The optimal cut-off value of PNI for OS stratification was determined to be 52.48. A total of 464 and 260 patients were assigned to low and high PNI groups, respectively. Compared with low PNI, high PNI was associated with older age, advanced stage, and elevated lactate dehydrogenase (LDH). Median overall survival (OS) was worse in the low PNI group (low vs high, 15.90 vs 25.27 months; HR, 0.62; p < 0.001). In multivariate analysis, stage, performance status, LDH, and PNI were independent prognostic factors for OS. Subgroup analysis showed PNI was generally a significant prognostic factor in different clinical situations. The assessment of PNI could assist the identification of patients with poor prognosis and be a hierarchical factor in the future SCLC clinical trials.

BackgroudProgrammed cell death-ligand 1 (PD-L1) and driver mutations are commonly seen in non-small-cell lung cancer (NSCLC). However, the prevelance of PD-L1 over-expression and its prognostic value in Epstein–Barr virus (EBV) associated pulmonary lymphoepithelioma-like carcinoma (LELC) remains poorly understood.MethodsA total of 214 NSCLC patients and 113 surgically treated pulmonary LELC patients were included. Paraffin-embedded tumor sections were stained with PD-L1 antibody. Correlations between PD-L1 expression and clinicopathological features as well as survival outcomes were analyzed.ResultsThe frequency of PD-L1 over-expression in NSCLC was 51.4%. No significant association was observed between common driver mutations and PD-L1 over-expression. Remakably, the positive rate of PD-L1 in pulmonary LELC was 74.3%. High PD-L1 expression was associated with impaired diseas-free survival (DFS) compared with low PD-L1 expression (p = 0.008). Multivariate analysis shows that PD-L1 expression level, N stage and M stage were independent prognostic factors for DFS. N stage and M stage but not PD-L1 expression level were significantly associated with overall survival (OS).ConclusionsPD-L1 over-expression was not related to common driver mutations in NSCLC. Pulmonary LELC have remarkably high incidence of PD-L1 expression. PD-L1 was a negative prognostic factor for DFS in surgically resected pulmonary LELC. These findings may provide a rationale for immunotarget therapy in this virus-associated lung cancer.

For advanced NSCLC patients with EGFR mutations, nonsmoking is associated with longer PFS than ever smoking after EGFR-TKIs treatment. Smoking history should be considered an essential factor in studies regarding EGFR-targeted agents toward EGFR-mutant patients.

Current guidelines for lung cancer treatment with EGFR tyrosine kinase inhibitors (TKI) include only patients with mutated EGFR, although some patients with wildtype EGFR (wt-EGFR) have exhibited positive responses to this therapy as well. Biomarkers predicting the benefit from EGFR-TKIs treatment remain to be determined for patients with wild-type EGFR.Here, we report that wt-EGFR overexpression transformed cells in vitro and induced tumorigenesis in vivo in transgenic mouse models. Wt-EGFR driven lung cancer was hypersensitive to TKI treatment in mouse model. Lung cancer patients with high-expression of wt-EGFR showed longer Overall Survival in comparison to low-expression patients after TKI treatment. Our data therefore suggest that treatment with EGFR inhibitors should be extended to include not only patients with mutated EGFR but also a subset of patients with overexpression of wt-EGFR.