Regulation Of Tumor Immunity Research Articles

Increased OIT3 in macrophages promotes PD-L1 expression and hepatocellular carcinogenesis via NF-κB signaling

Oncoprotein-induced transcript 3 (OIT3) facilitates macrophage M2 polarization and hepatocellular carcinoma (HCC) progression, however, whether OIT3 regulates tumor immunity remains largely unknown. Here we found that OIT3 was upregulated in HCC-associated macrophages, which inhibited CD4+ and CD8+ T-cell infiltration in the tumor microenvironment (TME). Mechanistically, OIT3 increased the expression of PD-L1 on tumor-associated macrophages (TAMs) by activating NF-κB signaling, blockade of NF-κB reversed the immunosuppressive activity of TAMs and dampens HCC tumorigenesis. Our findings provide the molecular basis for OIT3 enhancing tumor immunosuppression and highlighted a potential therapeutic strategy for targeting the TAMs of HCC.

Neutrophils as key regulators of tumor immunity that restrict immune checkpoint blockade in liver cancer.

Liver cancer is a deadly malignancy associated with high mortality and morbidity. Less than 20% of patients with advanced liver cancer respond to a single anti-PD-1 treatment. The high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade (ICB). However, the underlying mechanism remains largely unknown. We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12D into the genome in liver cells from conditional Trp53 null/null mice (pTMK/Trp53-/-). Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor microenvironment. An ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils (TANs) on CD8+ T cells. The roles of neutrophils, T cells, and NK cells were validated through antibody-mediated depletion. The efficacy of the combination of neutrophil depletion and ICB was evaluated. Orthotropic pTMK/Trp53-/- mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 blockade. Depletion of neutrophils increased the infiltration of CD8+ T cells and decreased the number of exhausted T cells in the tumor microenvironment. Furthermore, depletion of either CD8+ T or NK cells abrogated the antitumor efficacy of anti-Ly6G treatment. Moreover, the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8+ T cells and thereafter resulted in a significantly greater decrease in tumor burden. Our data suggest that TANs may contribute to the resistance of liver cancer to ICB, and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.

Effect of tumor microenvironment on ferroptosis: inhibition or promotion.

Ferroptosis is a type of lipid peroxidation-induced, iron-dependent programmed cell death. Emerging evidence suggests that ferroptosis is intimately connected to tumorigenesis, development, treatment and plays a major role in tumor immune regulation. This study focused on the connection between ferroptosis and immune regulation, which may offer a theoretical basis for targeting ferroptosis and tumor immunotherapy.

MiR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and Tcells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing Tcells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic Tcells and reduced regulatory Tcells (Treg). Moreover, depleting cytotoxic Tcells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.

H3K4me3-related lncRNAs signature and comprehensive analysis of H3K4me3 regulating tumor immunity in lung adenocarcinoma

BackgroudThe role of epigenetic modifications in tumorigenesis has been widely reported. However, the role and mechanism of H3K4me3 modification in lung adenocarcinoma (LUAD) are rarely reported systematically. We, therefore, sought to analyze the characteristics of LUAD associated with H3K4me3 modification, build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD and clarify the potential value of H3K4me3 in immunotherapy of LUAD.MethodsWe evaluated H3K4me3-lncRNA patterns and H3K4me3-lncRNA scores of 477 LUAD samples based on 53 lncRNAs closely correlated to H3K4me3 regulators and comprehensive analyzed the role of these patterns in tumorigenesis and tumor immunity. Using Gene set variation analysis (GSVA), we systematically evaluated the H3K4me3 level of every sample and deeply analyzed the effect of H3K4me3 on the prognosis of LUAD. In addition, we included two independent immunotherapy cohorts to study the impact of high H3K4me3 score on the prognosis of patients. We also used an independent cohort with 52 matched paraffin specimens of LUAD to verify the impact of high H3K3me3 expression on the prognosis of patients.ResultsWe identified three H3K4me3-lncRNA patterns that exhibited specific immune characteristics. Characterized by immunosuppressive and increased TGFβ-mediated epithelial-mesenchymal transition (EMT), patients with high H3K4me3-lncRNA score had a poor overall survival and decreased H3K4me3 score. H3K4me3 score was significantly positively correlated with CD4+T-cell and CD8+T-cell activation, programmed cell death and immune checkpoints (ICs) expression, and was negatively correlated with MYC pathway, TP53 pathway, and cell proliferation. Patients with high H3K4me3 score showed elevated expression of ICs, potentiated CD4 T-cell and CD8 T-cell activation, increased programmed cell death, and suppressed cell proliferation and TGFβ-mediated EMT. Patients with high H3K4me3 score and high expression of CTLA4, ICOS, TIGIT, PDCD1LG2, IDO1, CD274, PDCD1, LAG3, or HAVCR2 had the best survival advantage. Two independent immunotherapy cohorts verified that patients with high H3K4me3 score showed an increased inflamed tumor microenvironment (TME) phenotype and enhanced anti-PD-1/L1 immunotherapy response. Immunohistochemistry (IHC) data from 52 matched paraffin specimens of LUAD confirmed that the protein level of H3K4me3 in tumor was significantly lower than that of paracancerous tissues and H3K4me3 brought significant survival benefits to patients with LUAD.ConclusionsWe build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD. More importantly, this study revealed characteristics of H3K4me3 modification in LUAD and clarified the important potential role of H3K4me3 on tumor immunotherapy and patients’ survival.

CD244 loss on monocytes promotes differentiation into M1 macrophages and potentiates PD-L1 blockade in melanoma

Abstract Accumulating data have highlighted the role of monocytes/macrophages in immune escape by generating immunologically “cold” tumors that do not respond to immunotherapy. CD244 (SLAMF4, 2B4), a member of the signaling lymphocyte activation molecule family, is expressed on myeloid cells, but its precise role has not been elucidated. Using monocyte lineage-specific CD244-deficient micechallenged with B16F10 melanoma, we report for the first time that CD244 negatively regulates tumor immunity by inhibiting the differentiation and functional maturation of monocytes into macrophageswithin the tumor microenvironment. CD244-deficient macrophages more effectively activated antigen-specific T cell responsescompared to WT macrophages, thus delaying tumor growth in the B16F10 melanoma model. Moreover, combinatorial intervention of anti-PD-L1 antibodies with CD244-KO BMDM markedly improved tumor rejectioncompared to the anti-PD-L1 antibody alone or in combination with WT BMDM. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset, revealed DEGs of CD244 −monocytes and macrophages were associated with phagocytosis, antigen presentation, and autophagy. Additionally, cell type deconvolution analysis within melanoma patients bulk RNA-seq datasets from TCGA database, revealed presence of CD244-monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Hence, we proposed that CD244 serve as a critical immunoregulatory receptor on macrophages, and CD244-deficient macrophages may represent a novel therapeutic modality, which can function synergistically with checkpoint blockade therapies. Supported by grants from National Research Foundation of Korea (NRF-2020R1A2C2103061, NRF-2018M3A9D3079288, NRF-2016M3A9B6948342)

Lysosomal lipid peroxidation regulates tumor immunity.

Lysosomal inhibition elicited by palmitoyl protein transferase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC), but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12, was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naïve T cells, and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells, engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.

Identification of a novel peptide targeting TIGIT to evaluate immunomodulation of 125I seed brachytherapy in HCC by near-infrared fluorescence.

Hepatocellular carcinoma (HCC) has very poor prognosis due to its immunosuppressive properties. An effective measure to regulate tumor immunity is brachytherapy, which uses 125I seeds planted into tumor. T cell immune receptors with immunoglobulin and ITIM domains (TIGIT) is highly expressed in HCC. The TIGIT-targeted probe is expected to be an effective tool for indicating immunomodulation of 125I seed brachytherapy in HCC. In this study, We constructed a novel peptide targeting TIGIT to evaluate the immune regulation of 125I seed brachytherapy for HCC by near-infrared fluorescence (NIRF). Expression of TIGIT by immunofluorescence (IF) and flow cytometry (FCM) in different part and different differentiated human liver cancer tissues was verified. An optical fluorescence probe (Po-12) containing a NIRF dye and TIGIT peptide was synthesized for evaluating the modulatory effect of 125I seed brachytherapy. Lymphocytes uptake by Po-12 were detected by FCM and confocal microscopy. The distribution and accumulation of Po-12 in vivo were explored by NIRF imaging in subcutaneous and orthotopic tumors. IHC and IF staining were used to verify the expression of TIGIT in the tumors. TIGIT was highly expressed in HCC and increased with tumor differentiation. The dye-labeled peptide (Po-12) retained a stable binding affinity for the TIGIT protein in vitro. Accumulation of fluorescence intensity (FI) increased with time extended in subcutaneous H22 tumors, and the optimal point is 1 h. TIGIT was highly expressed on lymphocytes infiltrated in tumors and could be suppressed by 125I seed brachytherapy. Accumulation of Po-12-Cy5 was increased in tumor-bearing groups while declined in 125I radiation group.

Immune cell death-related lncRNA signature as a predictive factor of clinical outcomes and immune checkpoints in gastric cancer.

Background: Immune cell death (ICD) is a type of tumor cell death that has recently been shown to activate and regulate tumor immunity. However, the role of ICD-related long non-coding RNAs (lncRNAs) in gastric cancer remains to be clarified. Methods: We obtained 375 tumor samples from the Cancer Genome Atlas (TCGA) database and randomly assigned them to training and verification groups. LASSO and Cox regression analysis were utilized to identify ICD-related lncRNAs and establish a risk model. The changes in the immune microenvironment of the two groups were compared by examining the tumor-infiltrating immune cells. Results: We established a tumor signature based on nine ICD-related lncRNAs. In light of the receiver operating characteristic and Kaplan-Meier curves, the prognostic values of this risk model were verified. Multivariate regression analysis showed that the risk score was an independent risk factor for the prognosis of patients in both the training cohort (HR 2.52; 95% CI: 1.65-3.87) and validation cohort (HR 2.70; 95% CI: 1.54-4.8). A nomogram was developed to predict the 1-, 3-, and 5-year survival of patients with gastric cancer, and the signature was linked to high levels of immunological checkpoint expression (B7-H3, VSIR). Conclusions: An ICD-related lncRNA signature could predict the immune response and prognosis of patients with gastric cancer. This prognostic signature could be employed to independently monitor the efficacy of immunotherapy for gastric cancer patients.

DISC1 as a prognostic biomarker correlated with immune infiltrates in gastric cancer

Multiple mental diseases could arise in people who have the disrupted in schizophrenia 1 (DISC1) gene. However, it was unknown how DISC1 might contribute to the development of tumors and immune responses. We extracted data from the Cancer Genome Atlas (TCGA) and TISIDB databases from stomach adenocarcinoma (STAD) patients, which revealed that DISC1 overexpression was closely associated with tumor histological type (mucinous vs. tubular, OR = 2.860, CI = 1.423–5.872, p = 0.004), as well as tumor stage and grade. Furthermore, the higher the DISC1 expression, the lower the overall 10-year survival rate. Patients with low DISC1 expression had a significantly longer progression-free interval (PFI) and disease-specific survival (DSS) than patients with high DISC1 expression. However, patients with higher DISC1 expression in the T3&T4, N0&N1 and M0 subgroups had poorer prognosis in terms of OS, DSS and PFI, as could be seen in the subgroup survival analysis. Public datasets were used to predict lncRNA-miRNA-DISC1 regulation. DISC1 was significantly up-regulated in GC(gastric cancer), and its expression levels showed a moderate to strong positive correlation with infiltration levels of effector memory T cells (Tem) and central memory T cells (Tcm), and a negative correlation was observed with Th17 cells and NK CD56bright cells. In addition, concomitant with the high expression of the DISC1 gene was a decrease in MHC-I (Major Histocompatibility Complex-I)expression and an increase in MHC-II expression, and altered chemokine expression. The upregulation of CXCL12 and CXCR4 expression could be caused by an increase in DISC1 expression.The above expression variability and correlation suggest a role for DISC1 in regulating tumor immunity in GC. These findings suggest that high expression of DISC1 could be an independent prognostic factor for GC.

Targeting YAP/TAZ in Combination with PD-L1 Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

The survival of non-small cell lung cancer (NSCLC) patients has improved in the last decade as a result of introducing new therapeutics, such as immune checkpoint inhibitors, in the clinic. Still, some NSCLC patients do not benefit from these therapies due to intrinsic resistance or the development of acquired resistance and their malignant disease progresses. Further research on the molecular underpinnings of NSCLC pathobiology is required in order to discover clinically relevant molecular targets that regulate tumor immunity and to develop reasonable therapeutic combinations that will promote the efficacy of immune checkpoint inhibitors. Yes-associated Protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as key players in NSCLC development and progression. Herein, we overview studies that have investigated the oncogenic role of YAP/TAZ in NSCLC, focusing on immune evasion, and highlight the therapeutic potential of combining YAP/TAZ inhibitory agents with immune checkpoint inhibitors for the management of NSCLC patients.

Development of a nomogram based on serum cytokine-related riskscore in breast cancer.

Cytokines are involved in many inflammatory diseases and thus play an important role in tumor immune regulation. In recent years, researchers have found that breast cancer is not only related to genetic and environmental factors, but also to the chronic inflammation and immunity. However, the correlation between serum cytokines and blood tests indicators remain unclear. A total of 84 serum samples and clinicopathological data of breast cancer patients from Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, P. R. China were collected. The expression levels of the 12 cytokines were detected by immunofluorescence method. Blood tests results were obtained from medical records. By stepwise Cox regression analysis, a cytokine-related gene signature was generated. Univariate and multivariate Cox regression were used to analyze the influence on the prognosis of patients. A nomogram was constructed to illustrate the cytokine-related riskscore predicting 5-year OS, which was further evaluated and validated by C-index and ROC curve. The correlation between the expression of cytokines in serum and other blood indicators was studied by using Spearman's test. The riskscore was calculated as IL-4×0.99069 + TNF-α×0.03683. Patients were divided into high and low risk groups according to the median riskscore, with the high-risk group has a shorter survival time by log-rank test (training set, P=0.017; validation set, P=0.013). Combined with the clinical characteristics, the riskscore was found to be an independent factor for predicting the OS of breast cancer patients in both training cohort (HR=1.2, P<0.01) and validation cohort (HR=1.6, P=0.023). The 5-year C-index and AUC of the nomogram were 0.78 and 0.68, respectively. IL-4 was further found to be negatively correlated with ALB. In summary, we have developed a nomogram based on two cytokines including IL-4 and TNF-α to predict OS of breast cancer and investigated their correlation with blood test indicators.

Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103+DC cells.

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

Deciphering the potential roles of ferroptosis in regulating tumor immunity and tumor immunotherapy.

Cancer immunotherapies, including immune checkpoint inhibition (ICI) and adoptive immune cells therapy, are promising therapeutic strategies. They reactivate the function of immune cells and induce immune responses to attack tumor cells. Although these novel therapies benefited a large amount of cancer patients, many cancer patients have shown fair responses even resistance to cancer immunotherapies, limiting their wide clinical application. Therefore, it is urgent to explore the underlying mechanisms of low response and resistance of cancer immunotherapy to enhance their treatment efficacy. The programmed cell death (PCD) including the ferroptosis, has been demonstrated to play essential roles in antitumor immunity and in regulating the immune response to ICIs. Ferroptosis, a phospholipid peroxidation-mediated, iron-dependent membrane damage, exhibite three critical hallmarks: the oxidation of phospholipids, the lack of lipid peroxide repair capability and the overloading of redox-active iron. Notably, ferroptosis was found to plays important roles in regulating tumor immunity and response to immunotherapy. Therefore, targeting ferroptosis alone or in combination with immunotherapy may provide novel options to promote their antitumor efficacy. However, the effect of ferroptosis on tumor immunity and immunotherapy is affected by the interaction of ferroptosis and cancer cells, immune cells, tumor microenvironment (TME) and others. In this review, we summarized and discussed the critical roles of ferroptosis in regulating antitumor immunity, TME and in the improvement of the therapeutic efficacy of immunotherapy in cancers.

Prognostic Value of Liver Kinase B1 (LKB1) in Gastric Cancer-Associated Tumor Microenvironment Immunity

Liver kinase B1 (LKB1) is a tumor suppressor gene, the inactivation of which occurs frequently in different tumor types. However, whether LKB1 is associated with the clinical features of gastric cancer (GC) and regulating tumor immunity is unknown. In this study, we showed that LKB1 is highly expressed in the serum of healthy individuals (n = 176) compared to GC patients (n = 416) and is also associated with clinical outcomes and good survival rates in GC patients. Furthermore, genes associated with immune checkpoints and T cell activation, such as PD-1, PD-L1, CD8A, CD8B, CD28, and GZMM, were shown to be highly expressed in GC subgroups with high LKB1 expression. Compared with fresh gastric cancerous tissues, LKB1 was highly expressed in CD3+CD8+ and CD3+CD8+CD28+ T cells in fresh adjacent non-cancerous tissues. CD3+CD8+ T cells produced an IFN-γ anti-cancer immune response. Furthermore, the proportion of CD3+CD8+ T cells that expressed LKB had a positive correlation with IFN-γ expression. Moreover, GC patients with low LKB1 expression had a poor objective response rate, and worse progression-free survival and overall survival when treated with pembrolizumab. In conclusion, LKB1 may be a potential immune checkpoint in GC patients.

Dishevelled 2 regulates cancer cell proliferation and T cell mediated immunity in HER2-positive breast cancer

BackgroundDishevelled paralogs (DVL1, 2, 3) are key mediators of Wnt pathway playing a role in constitutive oncogenic signaling influencing the tumor microenvironment. While previous studies showed correlation of β-catenin with T cell gene expression, little is known about the role of DVL2 in modulating tumor immunity. This study aimed to uncover the novel interaction between DVL2 and HER2-positive (HER2+) breast cancer (BC) in regulating tumor immunity and disease progression.MethodsDVL2 loss of function studies were performed with or without a clinically approved HER2 inhibitor, Neratinib in two different HER2+ BC cell lines. We analyzed RNA (RT-qPCR) and protein (western blot) expression of classic Wnt markers and performed cell proliferation and cell cycle analyses by live cell imaging and flow cytometry, respectively. A pilot study in 24 HER2+ BC patients was performed to dissect the role of DVL2 in tumor immunity. Retrospective chart review on patient records and banked tissue histology were performed. Data were analyzed in SPSS (version 25) and GraphPad Prism (version 7) at a significance p < 0.05.ResultsDVL2 regulates the transcription of immune modulatory genes involved in antigen presentation and T cell maintenance. DVL2 loss of function down regulated mRNA expression of Wnt target genes involved in cell proliferation, migration, invasion in HER2+ BC cell lines (±Neratinib). Similarly, live cell proliferation and cell cycle analyses reveal that DVL2 knockdown (±Neratinib) resulted in reduced proliferation, higher growth arrest (G1), limited mitosis (G2/M) compared to non-targeted control in one of the two cell lines used. Analyses on patient tissues who received neoadjuvant chemotherapy (n = 14) further demonstrate that higher DVL2 expression at baseline biopsy pose a significant negative correlation with % CD8α levels (r = − 0.67, p < 0.05) while have a positive correlation with NLR (r = 0.58, p < 0.05), where high NLR denotes worse cancer prognosis. These results from our pilot study reveal interesting roles of DVL2 proteins in regulating tumor immune microenvironment and clinical predictors of survival in HER2+ BC.ConclusionOur study demonstrates potential immune regulatory role of DVL2 proteins in HER2+ BC. More in-depth mechanistic studies of DVL paralogs and their influence on anti-tumor immunity may provide insight into DVLs as potential therapeutic targets benefiting BC patients.

Integrated bioinformatics analyses identifying key transcriptomes correlated with prognosis and immune infiltrations in lung squamous cell carcinoma

BackgroundLung Squamous Cell Carcinoma (LUSC) is a major subtype of lung malignancies and is associated with the cause of cancer-mediated mortality worldwide. However, identification of transcriptomic signatures associated with survival-prognosis and immunity of tumor remains lacking MethodThe GSE2088, GSE6044, GSE19188, GSE21933, GSE33479, GSE33532, and GSE74706 were integrated for identifying differentially expressed genes (DEGs) with combined effect sizes. Also, the TCGA LUSC cohort was used for further analysis. A series of bioinformatics methods were utilized for conducting the whole study. ResultsThe 831 genes (such as DSG3, PKP1, DSC3, TPX2, and UBE2C) were found upregulated and the 731 genes (such as ABCA8, SELENBP1, FAM107A, and CACNA2D2) were downregulated in the LUSC. The functional enrichment analysis identifies the upregulated KEGG pathways, including cell cycle, DNA replication, base excision repair, proteasome, mismatch repair, and cellular senescence. Also, the key hub genes (such as EGFR, HRAS, JUN, CDH1, BRCA1, CASP3, RHOA, HDAC1, HIF1A, and CCNA2) were identified along with the eight gene modules that were significantly related to the protein–protein interaction (PPI). The clinical analyses identified that the overexpression group of CDH3, PLAU, PKP3, STIL, CALU, LOXL2, POSTN, DPP3, GALNT2, LOX, and ITPA are substantially associated with a poor survival prognosis and the downregulated group of IL18R1 showed a similar trend. Moreover, our investigation demonstrated that the survival-associated genes were correlated with the stromal and immune scores in LUSC, indicating that the survival-associated genes regulate tumor immunity. The survival-associated genes were genetically altered in 27% of LUSC patients and showed excellent diagnostic efficiency. Finally, the consistent expression level of CDH3, PLAU, PKP3, STIL, CALU, LOXL2, POSTN, DPP3, GALNT2, and ITPA were found in the TCGA LUSC cohort ConclusionsThe identification of key transcriptomic signatures can be elucidated by the crucial mechanism of LUSC carcinogenesis.

Genomic and immunogenomic analysis of three prognostic signature genes in LUAD

BackgroundSearching for immunotherapy-related markers is an important research content to screen for target populations suitable for immunotherapy. Prognosis-related genes in early stage lung cancer may also affect the tumor immune microenvironment, which in turn affects immunotherapy.ResultsWe analyzed the differential genes affecting lung cancer patients receiving immunotherapy through the Cancer Treatment Response gene signature DataBase (CTR-DB), and set a threshold to obtain a total of 176 differential genes between response and non-response to immunotherapy. Functional enrichment analysis found that these differential genes were mainly involved in immune regulation-related pathways. The early-stage lung adenocarcinoma (LUAD) prognostic model was constructed through the cancer genome atlas (TCGA) database, and three target genes (MMP12, NFE2, HOXC8) were screened to calculate the risk score of early-stage LUAD. The receiver operating characteristic (ROC) curve indicated that the model had good prognostic value, and the validation set (GSE50081, GSE11969 and GSE42127) from the gene expression omnibus (GEO) analysis indicated that the model had good stability, and the risk score was correlated with immune infiltrations to varying degrees. Multi-type survival analysis and immune infiltration analysis revealed that the transcriptome, methylation and the copy number variation (CNV) levels of the three genes were correlated with patient prognosis and some tumor microenvironment (TME) components. Drug sensitivity analysis found that the three genes may affect some anti-tumor drugs. The mRNA expression of immune checkpoint-related genes showed significant differences between the high and low group of the three genes, and there may be a mutual regulatory network between immune checkpoint-related genes and target genes. Tumor immune dysfunction and exclusion (TIDE) analysis found that three genes were associated with immunotherapy response and maybe the potential predictors to immunotherapy, consistent with the CTR-DB database analysis.ConclusionsFrom the perspective of data mining, this study suggests that MMP12, NFE2, and HOXC8 may be involved in tumor immune regulation and affect immunotherapy. They are expected to become markers of immunotherapy and are worthy of further experimental research.

Review to Understand the Crosstalk between Immunotherapy and Tumor Metabolism.

Immune checkpoint inhibitors have ushered in a new era of cancer treatment by increasing the likelihood of long-term survival for patients with metastatic disease and by introducing fresh therapeutic indications in cases where the disease is still in its early stages. Immune checkpoint inhibitors that target the proteins cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1/programmed death ligand-1 have significantly improved overall survival in patients with certain cancers and are expected to help patients achieve complete long-lasting remissions and cures. Some patients who receive immune checkpoint inhibitors, however, either experience therapeutic failure or eventually develop immunotherapy resistance. Such individuals are common, which necessitates a deeper understanding of how cancer progresses, particularly with regard to nutritional regulation in the tumor microenvironment (TME), which comprises metabolic cross-talk between metabolites and tumor cells as well as intracellular metabolism in immune and cancer cells. Combination of immunotherapy with targeted metabolic regulation might be a focus of future cancer research despite a lack of existing clinical evidence. Here, we reviewed the significance of the tumor microenvironment and discussed the most significant immunological checkpoints that have recently been identified. In addition, metabolic regulation of tumor immunity and immunological checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways were also incorporated to discuss the possible metabolism-based treatment methods being researched in preclinical and clinical settings. This review will contribute to the identification of a relationship or crosstalk between tumor metabolism and immunotherapy, which will shed significant light on cancer treatment and cancer research.

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

BackgroundPCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9’s oncogenic roles in melanoma and other cancers remain unclear.MethodsPCSK9’s association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9−/− mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations.ResultsPCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9−/− mice.ConclusionsTumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9’s oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.