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    Introduction of mutant TP53 related genes in metabolic pathways and evaluation their correlation with immune cells, drug resistance and sensitivity. Life sciences BACKGROUND:Although the relationship between TP53 mutation, TP53 metabolism pathways, and tumorigenesis has been investigated, pan-cancer analysis of TP53 mutations and related metabolism pathways is not completely available in common types of human cancers. Thus, this study was going to represent TP53 mutant-related metabolism genes and pathways in a pan-cancer study and investigate the relationship between selected genes and drug resistance. METHODS:The DNA-seq data, RNA-seq data, and clinical information of 12 types of cancer were downloaded from the cancer genome atlas (TCGA) database. GSE70479 data were obtained from GEO database for validation of our TCGA data. To evaluate the survival rate of patients, GEPIA2 was applied. The CCLE and GDSC database were used to investigate drug resistance and sensitivity. RESULTS:Our findings indicated that TTN, MUC16, and TP53 were present in 12 types of cancer with high level of mutation frequency which abundance of TP53 mutations was higher. Mutant TP53-related (mTP53) pathways and genes including PKM, SLC16A3, HK2, PFKP, PHGDH, and CTSC were obtained from enrichment analysis and interestingly, top pathways were associated with metabolism including glycolysis and mTORC1 pathway. Our results showed the expression of some candidate genes correlated with immune markers, prognosis, and drug resistance. CONCLUSIONS:Top mutant genes for 12 cancers were highlighted while TP53 was selected as top mutant gene, and metabolic genes associated with the TP53 mutation were identified that some of which are important in poor prognosis. In doing so, mutations in TP53 could run some metabolic pathways and drug resistance and sensitivity. 10.1016/j.lfs.2022.120650
    ZBTB46 defines and regulates ILC3s that protect the intestine. Nature RORγt is a lineage-specifying transcription factor that is expressed by immune cells that are enriched in the gastrointestinal tract and promote immunity, inflammation and tissue homeostasis. However, fundamental questions remain with regard to the cellular heterogeneity among these cell types, the mechanisms that control protective versus inflammatory properties and their functional redundancy. Here we define all RORγt immune cells in the intestine at single-cell resolution and identify a subset of group 3 innate lymphoid cells (ILC3s) that expresses ZBTB46, a transcription factor specifying conventional dendritic cells. ZBTB46 is robustly expressed by CCR6 lymphoid-tissue-inducer-like ILC3s that are developmentally and phenotypically distinct from conventional dendritic cells, and its expression is imprinted by RORγt, fine-tuned by microbiota-derived signals and increased by pro-inflammatory cytokines. ZBTB46 restrains the inflammatory properties of ILC3s, including the OX40L-dependent expansion of T helper 17 cells and the exacerbated intestinal inflammation that occurs after enteric infection. Finally, ZBTB46 ILC3s are a major source of IL-22, and selective depletion of this population renders mice susceptible to enteric infection and associated intestinal inflammation. These results show that ZBTB46 is a transcription factor that is shared between conventional dendritic cells and ILC3s, and identify a cell-intrinsic function for ZBTB46 in restraining the pro-inflammatory properties of ILC3s and a non-redundant role for ZBTB46 ILC3s in orchestrating intestinal health. 10.1038/s41586-022-04934-4
    RASA2 ablation in T cells boosts antigen sensitivity and long-term function. Nature The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment. 10.1038/s41586-022-05126-w