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LncRNA AL161431.1 is currently known as a factor that can promote epithelial-mesenchymal transition. However, its role in the prognosis, immune infiltration and progression of bladder cancer (BLCA)patients is still unclear. The expression of AL161431.1 is elevated in BLCA tissues compared to normal tissues according to the TCGA database. By combining this data with clinical information, patients with high AL161431.1 expression have more advanced clinicopathological stages and shorter survival periods. Furthermore, AL161431.1 was identified as an independent prognostic factor for bladder cancer. We further analyzed the differences in immune infiltration, tumor mutation burden (TMB), immune checkpoints, and sensitivity to immunotherapy between groups with different levels of AL161431.1 expression. Enrichment analysis demonstrated that AL161431.1 is associated with numerous immune signaling pathways. High expression of AL161431.1 in cancer tissues was confirmed by qRT-PCR. CCK8, transwell, and wound healing demonstrated the oncogenic effects of AL161431.1. In conclusion, AL161431.1 is associated with immune infiltration in bladder cancer and has the potential to become a biomarker for predicting the prognosis of BLCA.

Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB‐high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB‐high tumors. Our results thus indicate that TMB‐high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC. Colorectal cancer (CRC) tumors with high tumor mutation burden (TMB) often exhibit distinct molecular features, including lower KRAS and higher BRAF mutation frequencies, microsatellite instability (MSI), and a mutational signature linked to the CpG island methylator phenotype (CIMP). Analysis suggests that mutations in mismatch repair and DNA damage response genes may precede BRAF mutations, contributing to serrated pathway activation in these tumors.

LncRNA AL161431.1 is currently known as a factor that can promote epithelial-mesenchymal transition. However, its role in the prognosis, immune infiltration and progression of bladder cancer (BLCA)patients is still unclear. The expression of AL161431.1 is elevated in BLCA tissues compared to normal tissues according to the TCGA database. By combining this data with clinical information, patients with high AL161431.1 expression have more advanced clinicopathological stages and shorter survival periods. Furthermore, AL161431.1 was identified as an independent prognostic factor for bladder cancer. We further analyzed the differences in immune infiltration, tumor mutation burden (TMB), immune checkpoints, and sensitivity to immunotherapy between groups with different levels of AL161431.1 expression. Enrichment analysis demonstrated that AL161431.1 is associated with numerous immune signaling pathways. High expression of AL161431.1 in cancer tissues was confirmed by qRT-PCR. CCK8, transwell, and wound healing demonstrated the oncogenic effects of AL161431.1. In conclusion, AL161431.1 is associated with immune infiltration in bladder cancer and has the potential to become a biomarker for predicting the prognosis of BLCA.

Immune checkpoint blockade has achieved great success as a targeted immunotherapy for solid cancers. However, small molecules that inhibit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) binding are still being developed and have several advantages, such as high bioavailability. Previously, we reported a novel PD-1/PD-L1-inhibiting small compound, SCL-1, which showed potent antitumor effects on PD-L1 tumors. These effects were dependent on CD8 T-cell infiltration and PD-L1 expression on tumors. The present study investigated the in vivo antitumor activity of SCL-1 in various mouse syngeneic tumor models. Twelve syngeneic mice models of tumors, such as colon, breast, bladder, kidney, pancreatic, non-small cell lung cancers, melanoma, and lymphomas, were used for in vivo experiments. Tumor mutation burden (TMB) was analyzed by whole exome sequencing (WES) using reference DNA from mouse blood. The proportion of CD8 T-cells infiltrating tumors before and after treatment was assessed using flow cytometry and immunohistochemistry (IHC). SCL-1 had a markedly greater antitumor effect (11 sensitive tumors and 1 resistant tumor among the 12 tumor types) than the anti-mouse PD-1 antibody (8 sensitive tumors and 4 resistant tumors). In addition, the tumor growth inhibition rate (%) was more closely associated with TMB in the SCL-1 group than in the anti-PD-1 antibody group. Furthermore, in vivo experiments using PD-L1 gene knockout and lymphocyte-depletion technologies demonstrated that the antitumor activity of SCL-1 was dependent on CD8 T-cell infiltration and PD-L1 expression in tumors. SCL-1 has great potential as an oral immunotherapy that targets immune checkpoint molecules in cancer treatment.

Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMB high and TMB low tumors. Melanomas were enriched in “naive T-cell”, “effector memory T-cell”, “exhausted T-cell”, “resting Treg T-cell” and “Th1-like” signatures, irrespective of their BRAF , NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMB low patients could also benefit from such therapies.

To evaluate the predictive utility of N6-methyladenosine (m6A)-associated long non-coding RNAs (lncRNAs) for the prognosis and immunotherapy response in papillary renal cell carcinoma (pRCC). Transcriptomic data of pRCC samples were extracted from the TCGA database. The m6A-related lncRNAs were identified by Pearson correlation analysis. Univariate and LASSO regression analyses were used to develop a risk model. The discrimination and predictive ability were evaluated through survival analysis, ROC analysis and consensus clustering. Tumor mutation burden (TMB) and immune infiltration of the risk groups were compared. A prognostic nomogram was constructed using six m6A-related lncRNAs, and validated through calibration and decision curve analysis (DCA). The lncRNAs HCG25 and NOP14-AS1 were knocked down in a human pRCC cell line using specific siRNA constructs, and the proliferation and migration rates were assessed by the CCK-8 and transwell assays. We identified a total of 153 m6A-related lncRNAs in pRCC datasets, of which six were selected for constructing a m6A-related lncRNA pRCC prognostic model. Mutations in the SETD2 gene correlated with worse prognosis. Significant differences were observed in immune cell infiltration between the two risk groups. A clinical prognostic nomogram for pRCC was further established based on clinical variables. In vitro assays further showed that HCG25 and NOP14-AS1 regulate the proliferation and migration of pRCC cells. The results validated the discrimination ability of both the m6A-related lncRNA pRCC prognostic model and the pRCC clinical prognostic nomogram. We developed a clinical prognostic nomogram for pRCC using pRCC prognostic-associated m6A-related lncRNAs, which can be utilized for predicting the prognosis and immune landscape of pRCC patients.

BackgroundThere is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).MethodsPatients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.Results8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB<5: TMB 5 to <10: 0.95 (0.89 to 1.02), TMB 10 to <20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB<10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.ConclusionsAcross >8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.

Objective Although the tumor mutation burden (TMB) was reported as a biomarker for immunotherapy of various cancers, whether it can effectively predict the survival prognosis in breast cancer patients remains unclear. In this study, the prognostic value of TMB and its correlation with immune infiltration were explored by using multigroup studies. Methods The somatic mutation data of 986 breast cancer patients were obtained from TCGA database. Breast cancer patients were divided into a low-TMB group and a high-TMB group according to the quartile of TMB scores. The differentially expressed genes (DEGs) were identified by the “limma” R program. The CIBERSORT algorithm was utilized to estimate the immune cell fraction of each sample. The TIMER database was utilized to evaluate the association between CNVs of immune genes and tumor immune cell infiltration and the prognostic value of the immune cells in breast cancer. Results In breast cancer, TP53 , PIK3CA , TTN , CDH1 and other genes were the most important mutated genes. Higher survival rate of patients was found in the low-TMB group. Among the top 10 DEGs, three of them belong to the KRT gene family. GSEA enrichment analysis showed that MAPK, Hedgehog, mTOR, TGF-bate and GnRH signaling pathways were enriched in the low-TMB group. The infiltration levels of the most of immune cells were higher in the low-TMB group ( P  <  0.01 ). Higher expression of CCL18 and TRGC1 was correlated with poor prognosis. Breast cancer patients with CCL18 copy number variations, especially arm-level gains, showed significantly decreased immune cell infiltration. In the low B cell infiltration group, the survival prognosis of breast cancer patients was poor. Conclusions TMB is a potential prognosis marker in breast cancer. Immune-related gene CCL18 and TRGC1 are biomarkers of poor prognosis while immune (B cell) infiltration is a biomarker of good prognosis.

Immunity to solid tumors is associated with the hallmarks of cancer-associated inflammation and the ability of immune mechanisms to limit tumor progression. Application of expanded tumor-infiltrating lymphocyte adoptive T cell therapy (TIL ACT) in clinical trials is now practiced at many sites around the world. Prior to immune checkpoint blockade (ICB), an approximate 50% objective response rate was consistently observed across multiple institutions for patients with melanoma. This now-approved strategy approaches 35% in recent studies from the USA and 49% with more highly selected patients in Europe. Here, we focus on early TIL studies in non-melanoma epithelial neoplasms. Increased understanding of cancer immunology has allowed changes in the TIL expansion process to include: (1) initial generation of TIL from fragments, (2) use of specialized large-scale culture vessels, (3) use of the rapid expansion protocol to enable ‘young’ TIL prosecution, and (4) treatment regimens employing non-myeloablative (NMA) chemotherapy followed by brief interleukin-2 administration. NMA leads to homeostatic proliferation of the transferred T cells, engraftment, profound neutropenia and lymphopenia, and improved clinical outcome. A key success of TIL ACT relies on the quality, specificity, and number of pre-existing TIL. This, in turn, is highly influenced by the suppressive tumor microenvironment. Thus, any means to alter ‘cold tumor (non-T cell inflamed)’ to ‘hot tumor (T cell inflamed)’ is theoretically desirable to improve both the quality and quantity of TIL obtained before harvest. Combinations of other immunotherapies such as application of ICB, co-stimulatory molecule agonist antibodies, autophagy inhibition, and dendritic cell support strategies could provide additional­ improvements in TIL therapy and enable harnessing of the adaptive immune response to enhance the clinical outcome of TIL-ACT patients.

High-grade glioma is characterized by cell heterogeneity, gene mutations, and poor prognosis. Abnormal copper homeostasis affects the pathogenesis of glioma, but the underlying mechanisms and involved proteins are unknown. Here, we selected 90 copper-related proteins and verified their expression differences in glioma and normal tissues in TCGA cohort followed by GO and KEGG clustering analyses. We then developed and validated a prognostic model. Moreover, we examined the mutation burden of copper-related proteins and discussed the differences in the immune microenvironment in the high- and low-risk groups. Furthermore, we focused on STEAP2 and demonstrated that STEAP2 expression was relatively low in tumor tissues compared to normal tissues, implying a favourable prognosis. Our findings provide a foundation for future research targeting copper-related proteins and their immune microenvironment to improve prognosis and responses to immunotherapy.