Trp53 Mutation-Mediated mTORC1 Inhibition and Inflammation Suppression Confer Resistance to Checkpoint Immunotherapy
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ABSTRACT:
PROVIDER: PRJNA1255567 | ENA |
REPOSITORIES: ENA
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Project description:p53 is a critical tumor suppressor gene that inhibits cancer development by regulating cell cycle arrest, apoptosis, DNA repair, and metabolism. However, recent studies examining TP53 mutations in cancer immunotherapy have yielded inconsistent results, likely due to differences in tumor mutational burden (TMB) and the context-dependent roles of specific p53 mutants. In this study, we assessed the function of G242V and S258I Trp53 mutations in MC38 cells in the context of immunotherapy by generating Trp53 deletion and observed significantly enhanced responses to anti-PD-1 therapy. We next characterized how the Trp53 deletion in MC38 tumor cells alters the immune response. To this end, we performed single-cell RNA and paired single-cell TCR sequencing (scRNAseq and scTCRseq) of anti-PD-1 treated Trp53CON and Trp53KO MC38 tumors on day 11 after tumor cells inoculation.
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Project description:We analyzed miRNA-based shRNA off-target effects by transducing Trp53-/- MEFs at single- and high-copy with six well-characterized, potent and weak Trp53 shRNAs. To advance RNAi therapy for KRAS-mutant cancer, we developed a functionally validated library of siRNAs against RAS pathway genes that minimize off-target effects and enable combination gene silencing at low dose. We developed an in vivo model for real-time tracking of nanoparticle-based siRNA delivery and offer proof-of-principle that siRNA-mediated inhibition of a single gene (KRAS) or combinations of genes (A/B/C-RAF or KRAS+PIK3C-A/B) can impair the growth of KRAS-mutant colorectal cancer xenografts. Trp53-/- MEFs were transduced with LMP expressing Trp53 shRNAs at single copy (11-21% infection efficiency) and high copy (>98% infection efficiency), selected on puromycin and grown in absence of the selection agent before harvest. Uninfected Trp53-/- MEFs and Trp53-/- MEFs infected with an empty vector control served as M-bM-^@M-^\no shRNAM-bM-^@M-^] reference.
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Project description:Loss of Pten in the KrasG12D;Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated expression of wild type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (an MDM2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low grade ovarian cancer cells, wild type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing type I ovarian cancer and other cancers in humans where wild-type TP53 is expressed. A direct comparison of ovarian surface epithelia cells from three different genotype mice
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Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-bM-^@M-^\low/low/high/lowM-bM-^@M-^] or M-bM-^@M-^\LLHLM-bM-^@M-^]. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb Mouse embryo fibroblasts (MEFs) wild type or deficient in Tsc2 expressing a Tfeb shRNA or scrambled shRNA vector were treated with 25 nM rapamycin or vehicle (methanol) for 24 h under low serum conditions (0.1% FBS)
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Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells
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