Abstract:Highlights d Genome-scale in vivo CRISPR screens identified tumorintrinsic factors of oncogenesis d Prkar1a is a strong genetic driver of oncogenesis d Prkar1a loss altered the transcriptome and proteome in immune responses d Prkar1a mutation in cancer cells remodels the tumor microenvironment
“…For example, it has been recently shown that the mutations in PRKAR1A are a tumour intrinsic event leading to drastic alterations in the genetic programme of cancer cells, thereby remodelling the tumour microenvironment. 51 MAP3K1 mutations have an effect on low Th1 polarisation in breast cancer. 6 Fig.…”
Section: Resultsmentioning
confidence: 99%
“…For example, it has been recently shown that the mutations in PRKAR1A are a tumour intrinsic event leading to drastic alterations in the genetic programme of cancer cells, thereby remodelling the tumour microenvironment. 51 MAP3K1 mutations have an effect on low Th1 polarisation in breast cancer. 6 The top genes of which mutations positively correlate with MIRACLE include genes that are associated with differential survival in cancer subtypes, such as IDH1, CIC and FUBP1 in glioma, 44 whereas other genes associated with immune-evasion mechanisms that follow immunologic pressure such as mutations of antigen-presenting machinery transcripts previously described (i.e., B2M, VHL and CASP8).…”
Section: Genomics Events Associated With Miracle Scorementioning
Background
The balance between immune-stimulatory and immune-suppressive mechanisms in the tumour microenvironment is associated with tumour rejection and can predict the efficacy of immune checkpoint-inhibition therapies.
Methods
We consider the observed differences between the transcriptional programmes associated with cancer types where the levels of immune infiltration predict a favourable prognosis versus those in which the immune infiltration predicts an unfavourable prognosis and defined a score named Mediators of Immune Response Against Cancer in soLid microEnvironments (MIRACLE). MIRACLE deconvolves T cell infiltration, from inhibitory mechanisms, such as TGFβ, EMT and PI3Kγ signatures.
Results
Our score outperforms current state-of-the-art immune signatures as a predictive marker of survival in TCGA (n = 9305, HR: 0.043, p value: 6.7 × 10−36). In a validation cohort (n = 7623), MIRACLE predicts better survival compared to other immune metrics (HR: 0.1985, p value: 2.73 × 10−38). MIRACLE also predicts response to checkpoint-inhibitor therapies (n = 333). The tumour-intrinsic factors inversely associated with the reported score such as EGFR, PRKAR1A and MAP3K1 are frequently associated with immune-suppressive phenotypes.
Conclusions
The association of cancer outcome with the level of infiltrating immune cells is mediated by the balance of activatory and suppressive factors. MIRACLE accounts for this balance and predicts favourable cancer outcomes.
“…For example, it has been recently shown that the mutations in PRKAR1A are a tumour intrinsic event leading to drastic alterations in the genetic programme of cancer cells, thereby remodelling the tumour microenvironment. 51 MAP3K1 mutations have an effect on low Th1 polarisation in breast cancer. 6 Fig.…”
Section: Resultsmentioning
confidence: 99%
“…For example, it has been recently shown that the mutations in PRKAR1A are a tumour intrinsic event leading to drastic alterations in the genetic programme of cancer cells, thereby remodelling the tumour microenvironment. 51 MAP3K1 mutations have an effect on low Th1 polarisation in breast cancer. 6 The top genes of which mutations positively correlate with MIRACLE include genes that are associated with differential survival in cancer subtypes, such as IDH1, CIC and FUBP1 in glioma, 44 whereas other genes associated with immune-evasion mechanisms that follow immunologic pressure such as mutations of antigen-presenting machinery transcripts previously described (i.e., B2M, VHL and CASP8).…”
Section: Genomics Events Associated With Miracle Scorementioning
Background
The balance between immune-stimulatory and immune-suppressive mechanisms in the tumour microenvironment is associated with tumour rejection and can predict the efficacy of immune checkpoint-inhibition therapies.
Methods
We consider the observed differences between the transcriptional programmes associated with cancer types where the levels of immune infiltration predict a favourable prognosis versus those in which the immune infiltration predicts an unfavourable prognosis and defined a score named Mediators of Immune Response Against Cancer in soLid microEnvironments (MIRACLE). MIRACLE deconvolves T cell infiltration, from inhibitory mechanisms, such as TGFβ, EMT and PI3Kγ signatures.
Results
Our score outperforms current state-of-the-art immune signatures as a predictive marker of survival in TCGA (n = 9305, HR: 0.043, p value: 6.7 × 10−36). In a validation cohort (n = 7623), MIRACLE predicts better survival compared to other immune metrics (HR: 0.1985, p value: 2.73 × 10−38). MIRACLE also predicts response to checkpoint-inhibitor therapies (n = 333). The tumour-intrinsic factors inversely associated with the reported score such as EGFR, PRKAR1A and MAP3K1 are frequently associated with immune-suppressive phenotypes.
Conclusions
The association of cancer outcome with the level of infiltrating immune cells is mediated by the balance of activatory and suppressive factors. MIRACLE accounts for this balance and predicts favourable cancer outcomes.
“…Some scientists have used scRNA-seq to construct an immune map of cancer in TME, for example, Elham Azizi constructed an immune map of breast cancer by analyzing immune cells from eight types of breast cancer and normal tissues, blood and lymph nodes ( 60 ), and Zheng isolated T cells from tumors, adjacent normal tissues, and peripheral blood to depict the immune map of hepatocellular carcinoma ( 30 ). Study also found that Prkar1a mutations in tumors result in dramatic changes in the genetic program of cancer cells through scRNA-seq, thus reshaping the microenvironment of the tumor ( 61 ).…”
Section: Progress In the Application Of Scrna-seq In Tumor Microenvirmentioning
Cancer has been a daunting challenge for human beings because of its clonal heterogeneity and compositional complexity. Tumors are composed of cancer cells and a variety of non-cancer cells, which together with the extracellular matrix form the tumor microenvironment. These cancer-related cells and components and immune mechanisms can affect the development and progression of cancer and are associated with patient diagnosis, treatment and prognosis. As the first choice for the study of complex biological systems, single-cell transcriptional sequencing (scRNA-seq) has been widely used in cancer research. ScRNA-seq has made breakthrough discoveries in tumor heterogeneity, tumor evolution, metastasis and spread, development of chemoresistance, and the relationship between the tumor microenvironment and the immune system. These results will guide clinical cancer treatment and promote personalized and highly accurate cancer treatment. In this paper, we summarize the latest research progress of scRNA-seq and its guiding significance for clinical treatment.
“…Prkar1a encoding the alpha regulatory subunit of the cAMPdependent type I protein kinase emerges as the one whose loss enables tumor formation in mice with normal immune background by reshaping the favorable tumor microenvironment. [141] Screens in human acute myeloid leukemia cell lines revealed H3K9 methyltransferase SETDB1 as a novel cancer venerability gene that can negatively regulate innate immunity by repressing the retrotransposable elements, cytosolic RNA sensing, and interferon-induced apoptosis. [142] Liu et al showed that tumor-secreting IFNs adapt tumors sensitive to double stranded RNA (dsRNA) accumulation and susceptible to ADAR (RNA specific adenosine deaminase) loss.…”
Section: Crispr Screen In Tumor Cellsmentioning
confidence: 99%
“…[153] Myeloid-derived suppressor cells (MDSCs) can repress T cell function thus limiting the efficacy of T cell-based cancer immunotherapy. Genes that limit T cell proliferation and IFN-γ secretion were hunted by an In vivo mouse model Tumor gene activation enhances antigen presentation and T cell response [140] Gene knockout Immortalized hepatocyte In vivo mouse model Tumor gene loss enables tumor growth in immunocompetent host [141] Gene knockout Acute myeloid leukemia In vitro cell viability Essential tumor genes; innate immunity regulator [142] Gene knockout Tongue squamous cell carcinoma In vitro cell viability Tumor gene loss rescues the lethality of ADAR depletion [143] Only the most relevant studies relating to cancer immunology and immunotherapy were included.…”
Section: Crispr Screen In Other Immune Cellsmentioning
cancer immunology. Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) was tested to treat melanoma cancer patients in 1980s. [5] Monoclonal antibodies (mAbs) targeting tumor-specific or highly expressed surface antigens were approved by the U.S. Food and Drug Administration (FDA) for cancer treatment in late 1990s, for example, mAb Rituximab targeting B cell marker CD20 was approved in 1997 for non-Hodgkin's lymphoma and mAb Trastuzumab (Herceptin) targeting highly expressed human epidermal growth factor like receptor 2 (HER2) was approved in 1998 for HER2-positive breast cancer. Cytokines like interleukin-2 (IL-2) that can augment the anti-tumor immune response were also approved in 1998 to treat metastatic melanoma patients. The first FDAapproved cancer vaccine was developed in 2010 under the brand name of 'Provenge' (sipuleucel-T) that works as an autologous dendritic cell-based vaccine for the treatment of advanced prostate cancer. In the following year, the first immune checkpoint inhibitor anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibody was approved as a novel licensed drug for treating metastatic melanoma. Therapies with genetically engineered T cells expressing chimeric antigen receptor (CAR-T cell therapy) also stepped onto stage as approved cancer drugs in 2017 with the first one "Kymriah" targeting a B cell antigen CD19 for the treatment of refractory pre-B cell acute lymphoblastic leukemia and diffuse large B cell lymphoma. In addition, there are many ongoing immunotherapy clinical trials that have been showing impressive anti-tumor response and clinical benefits. With these explosive progresses in this field, Science magazine named cancer immunotherapy as "Breakthrough of the Year" in 2013. [6] Furthermore, the 2018 Nobel Prize in physiology and medicine was awarded to Dr. Allison and Dr. Honjo for their contributions to immune checkpoint cancer therapy. Genome editing technology is a fundamental platform for modern biomedical research, which enables people to precisely manipulate the genetic materials in cells or organisms. This technique can be either applied as research tools or ways of therapeutic intervention for gene therapy or engineered cell therapy. Several engineered nucleases such as zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and meganuclease have been designed to fulfill the DNA scissors function for genome editing, however, the editing efficiency, ease of use, timing and cost issues collectively limit
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