scholarly journals A balance score between immune stimulatory and suppressive microenvironments identifies mediators of tumour immunity and predicts pan-cancer survival

2020 ◽  
Author(s):  
Tolga Turan ◽  
Sarah Kongpachith ◽  
Kyle Halliwill ◽  
Jessica Roelands ◽  
Wouter Hendrickx ◽  
...  
Keyword(s):  
Cancer Survival ◽  
Predictive Marker ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Intrinsic Factors ◽  
Immune Infiltration ◽  
T Cell Infiltration ◽  
Inhibitory Mechanisms ◽  
Tumour Rejection ◽  
Cancer Outcome

Abstract 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.

scholarly journals A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linbang Wang ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Nian Zhou ◽  
Tianji Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Pearson Correlation ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Mcf7 Cells ◽  
Tumour Immunity ◽  
Immune Genes ◽  
Normal Tissues

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

scholarly journals The Yin and Yang of tumour-derived extracellular vesicles in tumour immunity

2020 ◽  
Author(s):  
Takayoshi Yamauchi ◽  
Toshiro Moroishi
Keyword(s):  
Extracellular Vesicles ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Host Immunity ◽  
Biological Processes ◽  
Small Particles ◽  
Tumour Immunity ◽  
Heterogeneous Nature ◽  
Yin And Yang ◽  
Cellular Components

Abstract Extracellular vesicles (EVs) are small particles that are naturally released from various types of cells. EVs contain a wide variety of cellular components, such as proteins, nucleic acids, lipids and metabolites, which facilitate intercellular communication in diverse biological processes. In the tumour microenvironment, EVs have been shown to play important roles in tumour progression, including immune system–tumour interactions. Although previous studies have convincingly demonstrated the immunosuppressive functions of tumour-derived EVs, some studies have suggested that tumour-derived EVs can also stimulate host immunity, especially in therapeutic conditions. Recent studies have revealed the heterogeneous nature of EVs with different structural and biological characteristics that may account for the divergent functions of EVs in tumour immunity. In this review article, we provide a brief summary of our current understanding of tumour-derived EVs in immune activation and inhibition. We also highlight the emerging utility of EVs in the diagnosis and treatment of cancers and discuss the potential clinical applications of tumour-derived EVs.

scholarly journals 580P AT1412, a patient-derived CD9 antibody promotes tumour immune infiltration and induces tumour rejection

2020 ◽  
Vol 31 ◽  
pp. S492
Author(s):  
R. Schotte ◽  
J. Villaudy ◽  
M. Kedde ◽  
W. Pos ◽  
K. Wagner ◽  
...  
Keyword(s):  
Immune Infiltration ◽  
Tumour Rejection

scholarly journals Past, Present and Future of Oncolytic Reovirus

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3219
Author(s):  
Louise Müller ◽  
Robert Berkeley ◽  
Tyler Barr ◽  
Elizabeth Ilett ◽  
Fiona Errington-Mais
Keyword(s):  
Immune Responses ◽  
Therapeutic Agent ◽  
Tumour Microenvironment ◽  
Oncolytic Viruses ◽  
Full Potential ◽  
Cellular Mechanisms ◽  
Tumour Immunity ◽  
Combination Strategies ◽  
Significant Attention ◽  
Promising Therapeutic Agent

Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a “one size fits all” approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.

scholarly journals Recent Advances: The Imbalance of Immune Cells and Cytokines in the Pathogenesis of Hepatocellular Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 338
Author(s):  
Kumar Jayant ◽  
Nagy Habib ◽  
Kai W. Huang ◽  
Jane Warwick ◽  
Ramesh Arasaradnam
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Liver Parenchyma ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Inflammatory State

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

scholarly journals The Oncogenic Role and Immune Infiltration for CARM1 Identified by Pancancer Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Kui Liu ◽  
Jing Ma ◽  
Jiao Ao ◽  
Lili Mu ◽  
Yixian Wang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Squamous Cell ◽  
Immune Modulation ◽  
Lung Squamous Cell Carcinoma ◽  
Predictive Biomarker ◽  
Protein Arginine Methyltransferases ◽  
Immune Infiltration ◽  
T Cell Infiltration

Chromatin-modifying enzymes, especially protein arginine methyltransferases (PRMTs), have been identified as candidate targets for cancer. Cellular or animal-based evidence has suggested an association between coactivator-linked arginine methyltransferase 1 (CARM1) and cancer progression. However, the relationship between CARM1 and patient prognosis and immune infiltration in pancancer patients is unknown. On the basis of the GEO and TCGA databases, we first investigated the possible oncogenic functions of CARM1 in thirty-three tumor types. CARM1 expression was elevated in many types of tumors. In addition, there was a significant association between CARM1 expression and the survival rate of tumor patients. Uterine corpus endometrial carcinoma (UCES) samples had the highest CARM1 mutation frequency of all cancer types. In head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC), CARM1 expression was associated with the level of CD8+ T cell infiltration, and cancer-associated fibroblast infiltration was also observed in other tumors including kidney renal papillary cell carcinoma (KIRC) and prostate adenocarcinoma (PRAD). CARM1 was involved in immune modulation and played an important role in the tumor microenvironment (TME). Furthermore, activities associated with RNA transport and its metabolism were included in the possible mechanisms of CARM1. Herein, our first pancancer research explores the oncogenic role of CARM1 in various tumors. CARM1 is associated with immune infiltrates and can be employed as a predictive biomarker in pancancer.

scholarly journals Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6000
Author(s):  
Daniel Fowler ◽  
Callum Nattress ◽  
Alba Southern Navarrete ◽  
Marta Barisa ◽  
Jonathan Fisher
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Cell Function ◽  
B Cell Lymphoma ◽  
Tumour Microenvironment ◽  
The Novel ◽  
Gene Engineering ◽  
Tumour Immunity ◽  
Car T Cells ◽  
Car T

Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs.

scholarly journals Immune Landscape of Invasive Ductal Carcinoma Tumour Microenvironment Identifies a Prognostic and Immunotherapeutically Relevant Gene Signature

2019 ◽  
Author(s):  
Xuanwen Bao ◽  
Run Shi ◽  
Kai Zhang ◽  
Shan Xin ◽  
Xin Li ◽  
...  
Keyword(s):  
Survival Probability ◽  
Cox Regression ◽  
Ductal Carcinoma ◽  
Gene Mutations ◽  
Tumour Microenvironment ◽  
Clinicopathological Features ◽  
Random Forest Algorithm ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Somatic Gene

AbstractBackgroundInvasive ductal carcinoma (IDC) is a clinically and molecularly distinct disease. Tumour microenvironment (TME) immune phenotypes play crucial roles in predicting clinical outcomes and therapeutic efficacy.MethodIn this study, we depict the immune landscape of IDC by using transcriptome profiling and clinical characteristics retrieved from The Cancer Genome Atlas (TCGA) data portal. Immune cell infiltration was evaluated via single-sample gene set enrichment (ssGSEA) analysis and systematically correlated with genomic characteristics and clinicopathological features of IDC patients. Furthermore, an immune signature was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm. A random forest algorithm was applied to identify the most important somatic gene mutations associated with the constructed immune signature. A nomogram that integrated clinicopathological features with the immune signature to predict survival probability was constructed by multivariate Cox regression.ResultsThe IDC were clustered into low immune infiltration, intermediate immune infiltration, and high immune infiltration by the immune landscape. The high infiltration group had a favourable survival probability compared with that of the low infiltration group. The low-risk score subtype identified by the immune signature was characterized by T cell-mediated immune activation. Additionally, activation of the interferon-α response, interferon-γ response and TNF-α signalling via the NFκB pathway was observed in the low-risk score subtype, which indicated T cell activation and may be responsible for significantly favourable outcomes in IDC patients. A random forest algorithm identified the most important somatic gene mutations associated with the constructed immune signature. Furthermore, a nomogram that integrated clinicopathological features with the immune signature to predict survival probability was constructed, revealing that the immune signature was an independent prognostic biomarker. Finally, the relationship of VEGFA, PD1, PDL-1 and CTLA-4 expression with the immune infiltration landscape and the immune signature was analysed to interpret the responses of IDC patients to immune checkpoint inhibitor therapy.ConclusionTaken together, we performed a comprehensive evaluation of the immune landscape of IDC and constructed an immune signature related to the immune landscape. This analysis of TME immune infiltration patterns has shed light on how IDC respond to immune checkpoint therapy and may guide the development of novel drug combination strategies.

Sign in / Sign up

Export Citation Format

Share Document