How the genomic landscape of a tumor shapes the formation of tertiary lymphoid structure (TLS) and how might TLS alter the clinical outcome or response to immunotherapy had not been systematically explored. Utilizing the genomic and transcriptome data of solid tumors on TCGA, we quantified TLS based on a previous identified 12-chemokine signature and evaluated its correlation with mutation/neoantigen burden, functional mutation of oncogenes and the presence of viral infection. Clinical data was integrated to decide the prognostic significance of TLS for different cancers after surgical treatment. Publicly available data (clinical and transcriptome data) of immunotherapy clinical trials involving melanoma and lung cancer were also collected to evaluate TLS’s association with therapeutic outcome. Mutation burden and predicted neoantigen counts were positively correlated with TLS scoring in multiple cancer types. Mutation in tumor suppressor genes (KEAP1, PBRM1) and genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B), immune regulation (SMAD4) or DNA repair (BRCA1, BRCA2, TP53BP1) correlated with TLS alteration in multiple tumor types, indicating the interaction between mutation landscape and TLS formation. Epstein-Barr virus (EBV) infection in gastric cancer and human papillomavirus (HPV) infection in Head and Neck squamous cell carcinoma were associated with increased TLS scoring. High TLS scoring predicted favorable prognosis in certain cancer after surgical treatment and improved response to immunotherapy in lung cancer and melanoma. Our findings unraveled the genomic properties associated with TLS formation in different solid tumors and highlighted the prognostic and predictive significance of TLS in surgical treatment and immunotherapy.

Background: Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods: Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results: We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion: These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

A number of studies have examined the association between tumor protein 53 (TP53) mutations and the clinical outcome in patients with non-small-cell lung cancer (NSCLC), although these have yielded conflicting results. In the present study, electronic databases updated to September 2015 were searched to find relevant studies. A meta‑analysis was performed on the eligible studies, which quantitatively evaluated the association between the TP53 mutations and the survival of patients with NSCLC. Subgroup and sensitivity analyses were performed. A total of 19 studies that involved a total of 6,084 patients with NSCLC were included. When the TP53 mutation group (n=1,406) was compared with the wild-type group (lacking TP53 mutations; n=1,965), the wild‑type group was associated with a significantly higher overall survival rate [hazard ratio (HR), 1.26; 95% confidence interval (CI) 1.12‑1.41, P<0.0001]. Significant benefits of overall survival in the wild‑type group were found in the subgroup involving patients with NSCLC in the early stages, including the I/II phases (HR, 1.93, 95% CI, 1.17‑3.19, P=0.01; heterogeneity, I2=0.0%, P=0.976) and patients with adenocarcinoma (HR, 3.06; 95% CI, 1.66‑5.62, P<0.0001; heterogeneity: I2=0.0%, P=0.976). This meta‑analysis has indicated that TP53 gene alteration may be an indicator of a poor prognosis in patients with NSCLC. Furthermore, the results also suggested that the role of TP53 mutations may differ according to different pathological types and clinical stages. The presence of these mutations may define a subset of patients with NSCLC appropriate for investigational therapeutic strategies.

The strong invasive and metastatic nature of non-small cell lung cancer (NSCLC) leads to poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) is involved in cell migration, motility and invasion. The object of this study is to investigate the involvement of CTHRC1 in NSCLC invasion and metastasis. A proteomic analysis was performed to identify the different expression proteins between NSCLC and normal tissues. Cell lines stably express CTHRC1, MMP7, MMP9 were established. Invasion and migration were determined by scratch and transwell assays respectively. Clinical correlations of CTHRC1 in a cohort of 230 NSCLC patients were analysed. CTHRC1 is overexpressed in NSCLC as measured by proteomic analysis. Additionally, CTHRC1 increases tumour cell migration and invasion in vitro. Furthermore, CTHRC1 expression is significantly correlated with matrix metalloproteinase (MMP)7 and MMP9 expression in sera and tumour tissues from NSCLC. The invasion ability mediated by CTHRC1 were mainly MMP7- and MMP9-dependent. MMP7 or MMP9 depletion significantly eradicated the pro-invasive effects mediated by CTHRC1 on NSCLC cells. Clinically, patients with high CTHRC1 expression had poor survival. CTHRC1 serves as a pro-metastatic gene that contributes to NSCLC invasion and metastasis, which are mediated by upregulated MMP7 and MMP9 expression. Targeting CTHRC1 may be beneficial for inhibiting NSCLC metastasis.

PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC) PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC)