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Background: Tumour-unrelated, virus-specific bystander CD8 + T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet., Methods: We studied the characteristics of bystander CD8 + TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy., Results: We show that bystander CD8 + TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8 + TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8 + TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8 + TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment., Conclusion: Thus, the study demonstrates that bystander CD8 + TILs can be repurposed by IL-15 for tumour immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study is to explore the association of Ki-67 and p53 expression with prognosis in non-small cell lung cancer (NSCLC) patients who underwent curative resection. We retrospectively identified 116 consecutive patients with stages I-III NSCLC who underwent curative resection at a single center from January 2007 to December 2012. Ki-67 and p53 expression was assessed by immunohistochemistry. Data on clinicopathologic features and survival were collected retrospectively. Ki-67 expression in 109 samples and p53 expression in 115 patients were analyzed. According to the results, 108 patients (99 %) showed at least some expression of Ki-67. The median Ki-67 expression level was 30 %. Positive p53 expression was observed in 91 (79 %) patients. Higher Ki-67 expression (>40 %) was significantly more frequent in male (26 vs. 4 % in female, p=0.002), ever-smoker (31 vs. 10 % in never-smoker, p=0.024), and non-adenocarcinoma (30 vs. 11 % of adenocarcinoma, p=0.012) patients. In univariable analysis, median disease-free survival (DFS) was shorter with higher Ki-67 expression (16.1 vs. 61.9 months in those with lower Ki-67 expression, p=0.005), and p53 expression did not show an association with DFS. Among 42 patients with stage I NSCLC who did not receive adjuvant chemotherapy, DFS was significantly worse in patients with higher Ki-67 expression (2-year DFS rate 57 vs. 88 %, p=0.018). In a Cox regression model, higher Ki-67 expression (>40 %) was a significant independent prognostic factor associated with poorer DFS (HR 2.9, 95 % CI 1.3-6.2) along with TNM stage and age. Higher Ki-67 expression (>40 %) showed an independent association with shorter DFS in NSCLC patients who underwent curative resection.

Hypoxia-inducible factor (HIF)-1α is a regulatory subunit of HIF-1 that is stabilized and activated under hypoxic conditions. In non-small cell lung cancer (NSCLC), over-expression of HIF-1α has been associated with poor overall survival. However, there is conflicting data on the role of HIF-1α as a prognostic factor. Some studies have demonstrated close association between the HIF-1α signal pathways and epidermal growth factor receptors (EGFRs). We evaluated the prognostic significance of HIF-1α expression in 178 NSCLC patients using tissue microarray in the context of EGFR gene copy number and protein expression status. EGFR gene copy number was evaluated using fluorescent in situ hybridization (FISH), and EGFR protein expression was determined using immunohistochemistry (IHC). The difference in overall survival (OS) between HIF-1α-positive and HIF-1α-negative groups was statistically significant in patients with low EGFR gene copy number and negative EGFR expression (log-rank test, P = 0.03). In univariate and multivariate analyses, HIF-1α was a significant worse prognostic factor for OS in patients with low EGFR gene copy number and negative EGFR expression (hazard ratio = 2.992; 95% CI, 1.113-8.045; P = 0.03 in univariate analysis and hazard ratio = 8.127; 95% CI, 1.874-35.251; P < 0.01 in multivariate analysis). The results demonstrated that the prognostic significance of HIF-1α should be validated in the context of EGFR status in NSCLC patients, and the gene and protein status of EGFR and HIF-1α will be important to help select patients most likely to derive the greatest clinical benefit from EGFR or HIF-1α targeted therapies., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.