Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and immunotherapy utilizing anti‐programmed death 1/‐programmed death ligand‐1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand‐1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand‐1 regulation with a particular focus on interferon gamma in an in vitro setting and in clinical samples. Our in vitro findings showed that interferon gamma upregulated programmed death ligand‐1 expression on solid tumor cells through the JAK‐signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen‐specific CTL against tumor cells. Following treatment of cells with anti‐programmed death ligand‐1 mAb after interferon gamma‐pre‐treatment, the reduced anti‐tumor CTL activity by interferon gamma reached a higher level than the non‐treatment control targets. In contrast, programmed death ligand‐1 expression on tumor cells also significantly correlated with epithelial‐mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand‐1 expression significantly positively correlated with the presence of CD8‐positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8‐positive T‐cell infiltration may be more responsive to anti‐programmed death 1/‐programmed death ligand‐1 mAb therapy.

Purpose The MET receptor is involved in the pathogenesis and progression of non-small-cell lung cancer (NSCLC). Clinical trials with MET inhibitors in NSCLC are planned with patient selection based on immunohistochemistry (IHC) and/or gene copy number assessment. Therefore, a detailed understanding of relationship between these markers and prognosis is essential. Methods This study included tumors from 189 NSCLC patients who underwent pulmonary resection (median follow-up 5.3 years). MET expression was evaluated by IHC on tissue microarrays and scored according to hybrid (H) score (range: 0–400) and by scoring system used in the MetMAb trial (≥50% of cells with moderate or strong staining). MET gene copy number was assessed by silver in-situ hybridization (SISH, N=140 patients). Results Median MET IHC H-score was 60 (range: 0–400; N=174). There were no associations between clinical and pathological characteristics, disease-free or overall survival according to median value (P=0.36 and P=0.38, respectively) or other cut-points. According to MetMAb scoring criteria, IHC positivity rate was 25%, again with no associations to clinico-pathological features nor survival. In 140 tumors evaluable for MET copy number, three (2.1%) showed gene amplification and 14 (10%) had tumors with average of 5 or more copies/nucleus. There were no associations of MET copy number with clinical characteristics, disease-free or overall survival with any analyzed cut-points. Correlation between MET copy number and protein expression was significant (Pearson’s r=0.42, P<0.0001). Conclusions There is a significant correlation between MET protein expression and MET gene copy number in operable NSCLC, but neither is associated with prognosis.

NCT01184807.

Introduction Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates. Information about FRA protein expression in metastatic Non-Small Cell Lung Cancer (NSCLC) is limited. We investigated FRA as a biomarker for pemetrexed-based chemotherapy and compared it to thymidylate synthase (TS), the main target of pemetrexed. Materials and Methods Pre-treatment tumor specimens from 207 NSCLC patients with advanced disease were assessed for FRA and TS protein expression by immunohistochemistry using the H-score (range: 0–300) and correlated to patients’ clinicopathological data, radiographic response (RECIST), progression-free survival (PFS) and overall survival (OS). Results Low total (cytoplasmic and nuclear) TS protein expression (H-score <210) was associated with improved PFS (median: 5.6 vs. 3.5 months; HR=0.6379, P=0.0131) and prolonged OS (median: 22.5 vs. 11.5 months; HR: 0.5680, P=0.0107). An association between lower TS levels and response to pemetrexed-based therapy was found: mean H-score 187±5, median 180 for responders vs. 201±4, median 210, P=0.0244. High intracellular FRA expression (H-score ≥ 110) was associated with prolonged OS (28.9 vs. 11.7 months, HR=0.5316, P=0.0040) and a trend for association with PFS (5.6 vs. 4.1 months, HR=0.7395, P=0.0801) was noted. Membranous FRA expression was seen in 83% of patients, moreover, high membranous expression (H-score ≥20) was associated with improved PFS (5.6 vs. 3.7 months, HR=0.6445, P=0.0306) and OS (22.1 vs. 11.5 months, HR=0.5378, P=0.0131). Conclusions A large number of NSCLC patients have high expression of FRA and/or low level of TS expression. Expression levels of FRA and TS were associated with clinical benefit from pemetrexed-therapy.

No abstract