PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

Wan, Huan; Xu, Bin; Zhu, Ni; Ren, Baozhong

doi:10.1177/0300891619868287

Cited by 38 publications

(21 citation statements)

References 21 publications

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“…Considering the changes in the TME between non-tumor and HCC (87,88), our Cluster C1 signature has shown a predictive advantage in distinguishing the specific eHCC immune cell (CD8 Tem and CTLs) infiltration level from non-tumor samples. In this respect, in line with previous studies (89)(90)(91)(92), these two immune cells (CD8 Tem and CTLs) markedly elucidated the immune characteristics of HCC initiation and progress, which has also shown benefit in improving patient prognosis in both eHCC and aHCC. Therefore, we infer that the effect of Cluster C1 signature on the eHCC patients is probably related to the remodeling of specific immune cells in the TME.…”

Section: Discussionsupporting

confidence: 80%

Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics

et al. 2021

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BackgroundThe incidence of hepatocellular carcinoma (HCC) is rising worldwide, and there is limited therapeutic efficacy due to tumor microenvironment heterogeneity and difficulty in early-stage screening. This study aimed to develop and validate a gene set-based signature for early-stage HCC (eHCC) patients and further explored specific marker dysregulation mechanisms as well as immune characteristics.MethodsWe performed an integrated bioinformatics analysis of genomic, transcriptomic, and clinical data with three independent cohorts. We systematically reviewed the crosstalk between specific genes, tumor prognosis, immune characteristics, and biological function in the different pathological stage samples. Univariate and multivariate survival analyses were performed in The Cancer Genome Atlas (TCGA) patients with survival data. Diethylnitrosamine (DEN)-induced HCC in Wistar rats was employed to verify the reliability of the predictions.ResultsWe identified a Cluster gene that potentially segregates patients with eHCC from non-tumor, through integrated analysis of expression, overall survival, immune cell characteristics, and biology function landscapes. Immune infiltration analysis showed that lower infiltration of specific immune cells may be responsible for significantly worse prognosis in HCC (hazard ratio, 1.691; 95% CI: 1.171–2.441; p = 0.012), such as CD8 Tem and cytotoxic T cells (CTLs) in eHCC. Our results identified that Cluster C1 signature presented a high accuracy in predicting CD8 Tem and CTL immune cells (receiver operating characteristic (ROC) = 0.647) and cancerization (ROC = 0.946) in liver. As a central member of Cluster C1, overexpressed PRKDC was associated with the higher genetic alteration in eHCC than advanced-stage HCC (aHCC), which was also connected to immune cell-related poor prognosis. Finally, the predictive outcome of Cluster C1 and PRKDC alteration in DEN-induced eHCC rats was also confirmed.ConclusionsAs a tumor prognosis-relevant gene set-based signature, Cluster C1 showed an effective approach to predict cancerization of eHCC and its related immune characteristics with considerable clinical value.

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Section: Discussionsupporting

confidence: 80%

Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics

et al. 2021

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“…PGC-1α is a key regulator of MB and regulates OXPHOS and FAO (the main metabolic characteristics of memory T cells) [ 94 ]. Activators of PGC-1α act synergistically with checkpoint inhibitors to increase ROS production in T cells by enhancing mitochondrial metabolic activity, thereby promoting the antitumor effects of T cells [ 95 , 96 ]. CD8+ TIL-overexpressing PGC1α can improve the quality and function of mitochondria, and restore the antitumor ability of depleted T cells [ 97 , 98 ].…”

Section: Enhanced Mitochondrial Metabolismmentioning

confidence: 99%

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

et al. 2021

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Chimeric antigen receptor T cell (CAR-T cell) therapy is a relatively new, effective, and rapidly evolving therapeutic for adoptive immunotherapies. Although it has achieved remarkable effect in hematological malignancies, there are some problems that remain to be resolved. For example, there are high recurrence rates and poor efficacy in solid tumors. In this review, we first briefly describe the metabolic re-editing of T cells and the changes in metabolism during the preparation of CAR-T cells. Furthermore, we summarize the latest developments and newest strategies to improve the metabolic adaptability and antitumor activity of CAR-T cells in vitro and in vivo.

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“…Matsumoto, T., et al believed that VGF is only expressed in neuroendocrine carcinoma-derived cells and can be used as a new serological diagnostic marker for pulmonary neuroendocrine tumors [ 65 ]. PGC-1α is a crucial transcription regulator of genes that control energy metabolism and mitochondrial biogenesis through its partner transcription factors: nuclear respiratory factors and PPARs [ 66 ]. Overexpression of PGC-1α enhanced the efficacy of PD-1 blockers in lung cancer [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation

Zeng

et al. 2021

BMC Pulm Med

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Background Differences in genetics and microenvironment of LUAD patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD. Methods In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD. Results According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, including mutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5), pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups. Conclusions Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD.

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PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

Cited by 38 publications

References 21 publications

Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics

Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation

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