Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

Yu, Xiaofei; Liu, Wenjie; Chen, Shixian; Cheng, Xueqian; Paez, Patrick A; Sun, Tuanwei; Yuan, Fang; Wei, Chunyan; Landry, Joseph W.; Poklepovic, Andrew; Bear, Harry D.; Subjeck, John R.; Repasky, Elizabeth A.; Guo, Chunqing; Wang, Xiangyang

doi:10.1136/jitc-2020-001595

Cited by 12 publications

(7 citation statements)

References 45 publications

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“…Consistent with our research, NLRC4 could also suppress tumor development while inducing antitumor immunity. In another study, Flagrp170, an artificially designed immunomodulator, showed protective antitumor immunity in an NLRC4-dependent manner ( Yu X. et al, 2021 ). Sutterwala et al demonstrated that NLRC4 enhanced inflammation in tumor-associated macrophages (TAMs) in a noninflammasome-dependent manner and the antimelanoma effects of IFN-γ produced by CD4 + and CD8 + T cells ( Janowski et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma

Liu

Shen

et al. 2022

Front. Genet.

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Pyroptosis, defined as programmed cell death, results in the release of inflammatory mediators. Recent studies have revealed that pyroptosis plays essential roles in antitumor immunity and immunotherapy efficacy. Long noncoding RNAs (lncRNAs) are involved in a variety of biological behaviors in tumor cells, although the roles and mechanisms of lncRNAs in pyroptosis are rarely studied. Our study aimed to establish a novel pyroptosis-related lncRNA signature as a forecasting tool for predicting prognosis and ascertaining immune value. Based on lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA), we performed Pearson’s correlation analysis to identify pyroptosis-related lncRNAs. After differentially expressed gene analysis and univariate Cox regression analysis, we selected prognosis-related and differentially expressed lncRNAs. Finally, we performed multivariate Cox regression analysis to establish the three pyroptosis-related lncRNA signature. Kaplan–Meier (KM) survival analyses and receiver operating characteristic (ROC) curves indicated the excellent performance for predicting the prognosis of LUAD patients. At the same time, we applied multidimensional approaches to further explore the functional enrichment, tumor microenvironment (TME) landscape, and immunotherapy efficacy among the different risk groups. A nomogram was constructed by integrating risk scores and clinical characteristics, which was validated using calibrations and ROC curves. Three lncRNAs, namely, AC090559.1, AC034102.8, and AC026355.2, were involved in this signature and used to classify LUAD patients into low- and high-risk groups. Overall survival time (OS) was higher in the low-risk group than in the high-risk group, which was also validated in our LUAD cohort from Shandong Provincial Hospital. TME landscape analyses revealed that a higher abundance of infiltrating immune cells and a greater prevalence of immune-related events existed in the low-risk group. Meanwhile, higher expression of immune checkpoint (ICP) genes, higher immunophenoscore (IPSs), and greater T cell dysfunction in the low-risk group demonstrated a better response to immunotherapy than the high-risk group. Combined with predictions from the Tumor Immune Dysfunction and Exclusion (TIDE) website, we found that LUAD patients in the low-risk group significantly benefited from programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) immune checkpoint blockade (ICB) therapy compared with those in the high-risk group. Furthermore, drug susceptibility analysis identified potential sensitive chemotherapeutic drugs for each risk group. In this study, a novel three pyroptosis-related lncRNA signature was constructed, which could accurately predict the immunotherapy efficacy and prognosis in LUAD patients.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma

Liu

Shen

et al. 2022

Front. Genet.

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“…Specifically, DMRclusters A, B, and C are characterized by immune-inflamed, immune-desert, and immune-excluded phenotypes, respectively. The immune-inflamed phenotype, or “hot tumor,” is characterized by the existence of a large number of immune cells in the TME ( Zhang et al, 2020b ; Gruber et al, 2020 ; Yu et al, 2021 ). The other two phenotypes, or “cold tumor,” show non-inflammatory infiltration.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer

Liang

et al. 2021

Front. Cell Dev. Biol.

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Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy.Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis.Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses.Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.

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“…For analysis of tumor-infiltrating immune cells, tumors were digested with collagenase D (10 μg/mL) and DNase I (100 μg/mL) for 1 h at 37˚C. Single cell suspensions were prepared for flow cytometry analysis as described ( 33 ).…”

Section: Methodsmentioning

confidence: 99%

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine

Qian

Liu

et al. 2023

Front. Immunol.

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We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.

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Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

Cited by 12 publications

References 45 publications

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma

Identification and Validation of a Three Pyroptosis-Related lncRNA Signature for Prognosis Prediction in Lung Adenocarcinoma

DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine

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