Immunogenomics Analysis Reveals that TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer

Jiang, Zhongshan; Liu, Zhixian; Li, Mengyuan; Cai, Chen; Wang, Xiaosheng

doi:10.1016/j.tranon.2018.07.012

Cited by 104 publications

(95 citation statements)

References 52 publications

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“…3 B). The result showed that TP53 had the highest mutation rate in GC, and has a significantly higher mutation rate in IM-L than in IM-H (Fisher's exact test, P = 0.04 (TCGA), P = 0.12 (ACRG)), which was consistent with our previous studies that TP53 mutations inhibit tumor immunity in GC [ 30 ]. MUC16 had the second highest mutation rate in GC and was also significantly higher in IM-L than in IM-H (Fisher's exact test, P = 0.002 (TCGA), P = 0.04 (ACRG)).…”

Section: Resultssupporting

confidence: 90%

“…3 A). This is in accordance with our previous study showing that various immune signatures positively correlated with the MAPK, focal adhesion and Calcium signaling pathways in GC [ 30 ]. In contrast, the IM-L GC subtype was impoverished in immune signatures but enriched in base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair ( Fig.…”

Section: Discussionsupporting

confidence: 94%

“…This indicates that the activities of these pathways could be negatively associated with GC immunity. In fact, our previous study has shown that the activity of MAPK pathways positively related with immune signatures, while the activity of the mismatch repair pathway negatively correlated with immune signatures in GC [ 30 ].

Fig.…”

Section: Resultsmentioning

confidence: 99%

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Classification of gastric cancers based on immunogenomic profiling

Liu

Jiang

et al. 2021

Translational Oncology

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Background Extensive evidence showed that gastric cancer (GC) is heterogeneous, and many studies have been focused on identifying GC subtypes based on genomic profiles. However, few studies have specifically explored the GC classification and predicted the classification accuracy that may help facilitate the optimal stratification of GC patients responsive to immunotherapy. Methods Using two publicly available GC genomics datasets, we classified GC on the basis of 797 immune related genes. Unsupervised and supervised machine learning methods were used to predict the classification. Results We identified two GC subtypes that we named as Immunity-High (IM-H) and Immunity- Low (IM-L), and demonstrated that this classification was duplicable and predictable by analyzing other datasets. IM-H subtype was characterized by greater immune cell infiltration, stronger immune activities, lower tumor purity, as well as worse survival prognosis compared to IM-L subtype. Besides the immune signatures, some cancer-associated pathways were hyperactivated in IM-H, including TGF-beta signaling pathway, Focal adhesion, Cell adhesion molecules (CAMs), Calcium signaling pathway, mTOR signaling pathway, MAPK signaling pathway and Wnt signaling pathway. In contrast, IM-L presented depressed immune signatures and increased activation of base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair pathways. Furthermore, we identified subtype-specific genomic or clinical features, and subtype-specific gene ontology and networks in IM-H and IM-L subtype. Conclusions We proposed and validated two reproducible immune molecular subtypes of GC, which has potential clinical implications for GC patient selection of immunotherapy.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 94%

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Classification of gastric cancers based on immunogenomic profiling

Liu

Jiang

et al. 2021

Translational Oncology

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“…The mutations of TP53 were mostly observed in non-immune class, and the proportion was only 5.4% in the immune activated subtype. Jiang et al [78] demonstrated that the TP53 mutation results in the depressed immune activity in gastric cancer, and the less active immune pathways and cell types are observed in TP53-mutated gastric cancer patients. Carlisle et al [79] also reported TP53 mutation correlates with the poor efficacy of immunotherapy after adjusting PD-L1 expression in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Immune Response Drives Outcomes in Prostate Cancer: Implications for Immunotherapy

Meng

Zhou

et al. 2020

Preprint

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Highlights 52 ◼ Immunotherapy could trigger a durable response in advanced prostate cancer, 53 but it only benefits a minority of patients; 54 ◼ Immune response drives recurrence-free survival outcomes in prostate cancer; 55 ◼ The robust molecular classification system helps identify more ideal patients 56 for delivering anti-PD-1/PD-L1 immunotherapy. 57 102 factors, three immunophenotypes were established with bulk tumor gene 103 expression profiles from public cohorts and a real-world AHMU-PC cohort. Our 104 results suggested that immune response drove outcomes in prostate cancer and 105 provided inspirations of immunotherapy for prostate cancer patients.

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“…( 20 ) It has previously been reported that there is a correlation between mtp53 and absence/reduced presence of immune cells in head and neck, and gastric cancers. ( 23–25 ) However, it is not known whether this is the functional outcome of wildtype p53 loss or a gain-of-function activity of mtp53. Since mtp53 is associated with genomic instability, we speculated that it may alter signaling through the cGAS/STING/TBK1/IRF3 pathway to permit the accumulation of cytoplasmic DNA without triggering IRF3 activation.…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Ghosh

Saha

Bettke

et al. 2020

Preprint

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29Mutations in the p53 tumor suppressor occur very frequently in human cancer. 30Often, such mutations lead to the constitutive overproduction of mutant p53 31 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We 32 have identified a novel mechanism by which mtp53 controls both cell-autonomous 33 and non-cell autonomous signaling to promote cancer cell survival and suppress 34 tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic 35 DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of 36 the innate immune response. We find that mtp53, but not wildtype p53, binds to 37 TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-38 induced activity. The association of mtp53 with TBK1 prevents the formation of a 39 trimeric complex between TBK1-STING-IRF3, which is required for activation, 40 nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown 41 restores TBK1 activity, resulting in the transcriptional induction of IRF3 target 42 genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune 43 signaling by mtp53 alters cytokine production resulting in immune evasion. 44 Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-45 autonomous and non-cell autonomous tumor control. Thus, overriding mtp53's 46 inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored 47 an oncogenic mtp53 protein that exhibits gain-of function activities.(5) Recently, it has been 62 reported that 91% of cancers that have a mtp53 allele have lost their second allele through 63 mutation or chromosomal loss.(6) Furthermore, the presence of mtp53 correlates with increased 64 chromosomal instability leading to loss of tumor suppressor genes and amplification of 65 oncogenes.(6, 7) 66 Aneuploidy is considered one of the hallmarks of cancer and is thought to play an 67 important role in driving tumor cell evolution.(8) Aneuploidy has been shown to provoke cell 68 cycle arrest, senescence, increased pro-inflammatory cytokine production and upregulation of 69 Natural Killer (NK) cell ligands in tumor cells, resulting in their subsequent killing by NK 70 cells.(9) In an in vivo setting, the increased production of pro-inflammatory cytokines coupled 71 with increased NK cell ligand expression permits the recruitment of immune cells and clearance 72 of abnormal cells.(10) Thus, in addition to the cell-autonomous mechanisms that suppress 73 genetic instability, cells also utilize non-cell autonomous mechanisms to signal their own 74 destruction.(9) However, chromosomal instability can give rise to micronuclei, which are prone 75 to rupturing and releasing the DNA into the cytoplasm.(11) DNA leaked into the cytoplasm is 76 recognized by the DNA binding protein, cyclic GMP-AMP synthase (cGAS), which in turn triggers 77 innate immune signaling that results in the production of type I interferons.(12) Mechanistically, 78 DNA promotes cGAS homodimerization and production of the secon...

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Immunogenomics Analysis Reveals that TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer

Cited by 104 publications

References 52 publications

Classification of gastric cancers based on immunogenomic profiling

Classification of gastric cancers based on immunogenomic profiling

Immune Response Drives Outcomes in Prostate Cancer: Implications for Immunotherapy

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

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