PD1/PD-L1 Axis in Uro-oncology

The immune system is important to control tumor development and progression in humans. However, tumor cells and cells of the tumor microenvironment can induce immune escape mechanisms including activation of immune checkpoints such as PD-1/PD-L1. Based on this knowledge, new immune therapies, including PD-1 and PD-L1 inhibition, have been developed and are already recommended as a standard treatment in metastatic bladder and kidney cancer patients. In addition to its role as a therapeutic target, PD-L1 seems to be a prognostic parameter although data are controversial. Only little is known about signaling pathways inducing PD-L1 expression in tumor cells on one hand and about its functional role for tumor cells itself. However, the understanding of the complex biological function of PD-L1 will improve therapeutic options in urological malignancies. This review is giving an overview of the current knowledge concerning the PD-1/PD-L1 axis in urological tumors including bladder, kidney, prostate, testicular and penile cancer.

Download Full-text

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

10.1101/285338 ◽

2018 ◽

Cited By ~ 1

Author(s):

Shinichi Mizuno ◽

Rui Yamaguchi ◽

Takanori Hasegawa ◽

Shuto Hayashi ◽

Masashi Fujita ◽

...

Keyword(s):

Immune Escape ◽

Cancer Hallmarks ◽

Whole Genomes ◽

Immune Therapies ◽

History Of ◽

Copy Number Changes ◽

Immune Related Genes ◽

Tumor Types ◽

Immune Escape Mechanisms

AbstractImmune reactions in the tumor micro-environment are one of the cancer hallmarks and emerging immune therapies have been proven effective in many types of cancer. To investigate cancer genome-immune interactions and the role of immuno-editing or immune escape mechanisms in cancer development, we analyzed 2,834 whole genomes and RNA-seq datasets across 31 distinct tumor types from the PanCancer Analysis of Whole Genomes (PCAWG) project with respect to key immuno-genomic aspects. We show that selective copy number changes in immune-related genes could contribute to immune escape. Furthermore, we developed an index of the immuno-editing history of each tumor sample based on the information of mutations in exonic regions and pseudogenes. Our immuno-genomic analyses of pan-cancer analyses have the potential to identify a subset of tumors with immunogenicity and diverse background or intrinsic pathways associated with their immune status and immuno-editing history.

Download Full-text

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.619242 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zaoqu Liu ◽

Libo Wang ◽

Long Liu ◽

Taoyuan Lu ◽

Dechao Jiao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chromatin Remodeling ◽

Vascular Invasion ◽

Immune Escape ◽

Immune Checkpoints ◽

Related Risk ◽

Tumorigenesis And Progression ◽

Immunosuppressive Cells ◽

Immune Escape Mechanisms ◽

Worse Prognosis

BackgroundFerroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.MethodsBased on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.ResultsWe identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.ConclusionWe identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

Download Full-text

Comprehensive Molecular Analyses of a Novel Mutational Signature Classification System with Regard to Prognosis, Genomic Alterations, and Immune Landscape in Glioma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.682084 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zaoqu Liu ◽

Taoyuan Lu ◽

Libo Wang ◽

Long Liu ◽

Lifeng Li ◽

...

Keyword(s):

Immune Escape ◽

Molecular Classification ◽

Idh1 Mutation ◽

Immune Checkpoints ◽

Chromosome 1P ◽

Molecular Features ◽

Public Datasets ◽

Carcinogenic Process ◽

Immunosuppressive Cells ◽

Immune Escape Mechanisms

Background: Glioma is the most common malignant brain tumor with complex carcinogenic process and poor prognosis. The current molecular classification cannot fully elucidate the molecular diversity of glioma.Methods: Using broad public datasets, we performed cluster analysis based on the mutational signatures and further investigated the multidimensional heterogeneity of the novel glioma molecular subtypes. The clinical significance and immune landscape of four clusters also investigated. The nomogram was developed using the mutational clusters and clinical characteristics.Results: Four heterogenous clusters were identified, termed C1, C2, C3, and C4, respectively. These clusters presented distinct molecular features: C1 was characterized by signature 1, PTEN mutation, chromosome seven amplification and chromosome 10 deletion; C2 was characterized by signature 8 and FLG mutation; C3 was characterized by signature 3 and 13, ATRX and TP53 mutations, and 11p15.1, 11p15.5, and 13q14.2 deletions; and C4 was characterized by signature 16, IDH1 mutation and chromosome 1p and 19q deletions. These clusters also varied in biological functions and immune status. We underlined the potential immune escape mechanisms: abundant stromal and immunosuppressive cells infiltration and immune checkpoints (ICPs) blockade in C1; lack of immune cells, low immunogenicity and antigen presentation defect in C2 and C4; and ICPs blockade in C3. Moreover, C4 possessed a better prognosis, and C1 and C3 were more likely to benefit from immunotherapy. A nomogram with excellent performance was also developed for assessing the prognosis of patients with glioma.Conclusion: Our results can enhance the mastery of molecular features and facilitate the precise treatment and clinical management of glioma.

Download Full-text

Immunogenomic pan-cancer landscape reveals immune escape mechanisms and immunoediting histories

Scientific Reports ◽

10.1038/s41598-021-95287-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shinichi Mizuno ◽

Rui Yamaguchi ◽

Takanori Hasegawa ◽

Shuto Hayashi ◽

Masashi Fujita ◽

...

Keyword(s):

Immune Escape ◽

Diverse Backgrounds ◽

Immune Therapies ◽

History Of ◽

Copy Number Changes ◽

Immune Related Genes ◽

Tumor Types ◽

Immune Escape Mechanisms ◽

Pan Cancer

AbstractImmune reactions in the tumor microenvironment are an important hallmark of cancer, and emerging immune therapies have been proven effective against several types of cancers. To investigate cancer genome-immune interactions and the role of immunoediting or immune escape mechanisms in cancer development, we analyzed 2834 whole genome and RNA sequencing datasets across 31 distinct tumor types with respect to key immunogenomic aspects and provided comprehensive immunogenomic profiles of pan-cancers. We found that selective copy number changes in immune-related genes may contribute to immune escape. Furthermore, we developed an index of the immunoediting history of each tumor sample based on the information of mutations in exonic regions and pseudogenes and evaluated the immunoediting history of each tumor. Our immuno-genomic analyses of pan-cancers have the potential to identify a subset of tumors with immunogenicity and diverse backgrounds or intrinsic pathways associated with their immune status and immunoediting history.

Download Full-text

Stromal Protein-Mediated Immune Regulation in Digestive Cancers

Cancers ◽

10.3390/cancers13010146 ◽

2021 ◽

Vol 13 (1) ◽

pp. 146

Author(s):

Pia Gamradt ◽

Christelle De La Fouchardière ◽

Ana Hennino

Keyword(s):

Immune Cells ◽

Immune Regulation ◽

Cancer Colorectal ◽

Immune Escape ◽

Current Knowledge ◽

Cancer Associated Fibroblasts ◽

Ecm Proteins ◽

Digestive Cancers ◽

Stromal Proteins ◽

Immune Escape Mechanisms

The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.

Download Full-text

Immune Escape Mechanisms in Non Small Cell Lung Cancer

Cancers ◽

10.3390/cancers12123605 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3605

Author(s):

Andrea Anichini ◽

Valentina E. Perotti ◽

Francesco Sgambelluri ◽

Roberta Mortarini

Keyword(s):

Lung Cancer ◽

Immune Evasion ◽

Immune Escape ◽

Early Stage ◽

Human Leukocyte ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Normal Lung ◽

Early Stage Nsclc ◽

Immune Escape Mechanisms

Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active immune escape mechanisms has been found even in the pre-invasive lesions that later progress to the main NSCLC histotypes. Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1/TH2 cytokine ratios, and immune contexture evolution. Analysis of large panels of LUAD vs. LUSC, of early stage NSCLC vs. normal lung tissue, of specific molecular subsets of NSCLC, and of distinct regions within the same tumor, indicates that all these processes of immune escape continue to evolve in the invasive stage of NSCLC, are associated with inter- and intra-tumor heterogeneity, and contribute to resistance to therapy by immune checkpoint blockade (ICB). In this review, we will discuss the most recent evidence on immune escape mechanisms developing from the precursor to invasive stage in NSCLC, and the contribution of immune evasion to resistance to ICB in lung cancer.

Download Full-text

Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives

Journal of Oncology ◽

10.1155/2019/9513701 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 6

Author(s):

Diego De Goycoechea ◽

Gregoire Stalder ◽

Filipe Martins ◽

Michel A. Duchosal

Keyword(s):

Hodgkin Lymphoma ◽

Immune Checkpoint ◽

Immune Escape ◽

Response Rates ◽

Genetic Alterations ◽

Immune Checkpoints ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Classical Hodgkin Lymphoma ◽

Immune Escape Mechanisms

Immune checkpoint inhibition (ICI) became one of the major breakthroughs in cancer treatment over the past decade and entered into therapy within standard oncohematology practice. ICI has demonstrated impressive response rates as salvage therapy in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and is now being tested as an adjunction to chemotherapy in the frontline settings. CHL exquisite sensitivity to PD-1/PD-L1 axis inhibition relies on a particular biological background. By contrast, non-Hodgkin lymphomas (NHL) have demonstrated heterogeneous response rates using ICI. These observations highlight discrepancies between various types of lymphomas in terms of genetic alterations, immune microenvironment interactions, and disease phenotype. This review aims to focus on cHL immune escape mechanisms, focusing on cHL biological sensitivity to PD-1 blockade. We will summarize the available data issued from clinical trials on ICI in cHL and its safety profile. Going beyond the current use of monoclonal antibodies (mAb) targeting immune checkpoints in clinical practice, we will offer an overview of new combinatory therapeutic perspectives where cHL immunotherapy may be considered.

Download Full-text

The Microenvironment in Epstein–Barr Virus-Associated Malignancies

Pathogens ◽

10.3390/pathogens7020040 ◽

2018 ◽

Vol 7 (2) ◽

pp. 40 ◽

Cited By ~ 16

Author(s):

Geok Tan ◽

Lydia Visser ◽

Lu Tan ◽

Anke Berg ◽

Arjan Diepstra

Keyword(s):

Tumor Cells ◽

Epstein Barr Virus ◽

Immune Escape ◽

Cell Types ◽

Barr Virus ◽

Adaptive Immune Cells ◽

Associated Malignancy ◽

Epstein Barr ◽

Immune Escape Mechanisms ◽

Different Cell Types

The Epstein–Barr virus (EBV) can cause a wide variety of cancers upon infection of different cell types and induces a highly variable composition of the tumor microenvironment (TME). This TME consists of both innate and adaptive immune cells and is not merely an aspecific reaction to the tumor cells. In fact, latent EBV-infected tumor cells utilize several specific mechanisms to form and shape the TME to their own benefit. These mechanisms have been studied largely in the context of EBV+ Hodgkin lymphoma, undifferentiated nasopharyngeal carcinoma, and EBV+ gastric cancer. This review describes the composition, immune escape mechanisms, and tumor cell promoting properties of the TME in these three malignancies. Mechanisms of susceptibility which regularly involve genes related to immune system function are also discussed, as only a small proportion of EBV-infected individuals develops an EBV-associated malignancy.

Download Full-text

35 Expression of Complex Gangliosides by Tumor Cells Contributes to Immune Escape Mechanisms and Tumor Growth

Cytokine ◽

10.1016/j.cyto.2007.07.040 ◽

2007 ◽

Vol 39 (1) ◽

pp. 10

Author(s):

Rafael Fernandez-Botran ◽

James G. Cripps ◽

Fabian A. Crespo

Keyword(s):

Tumor Growth ◽

Tumor Cells ◽

Immune Escape ◽

Immune Escape Mechanisms

Download Full-text

Single‐cell RNA sequencing in cancer research

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01874-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yijie Zhang ◽

Dan Wang ◽

Miao Peng ◽

Le Tang ◽

Jiawei Ouyang ◽

...

Keyword(s):

Single Cell ◽

Tumor Cells ◽

Rna Sequencing ◽

Immune Cells ◽

Immune Escape ◽

Tumor Development ◽

Cell Types ◽

Resistance Mechanisms ◽

Single Cell Rna Sequencing ◽

Tumor Research

AbstractSingle-cell RNA sequencing (scRNA-seq), a technology that analyzes transcriptomes of complex tissues at single-cell levels, can identify differential gene expression and epigenetic factors caused by mutations in unicellular genomes, as well as new cell-specific markers and cell types. scRNA-seq plays an important role in various aspects of tumor research. It reveals the heterogeneity of tumor cells and monitors the progress of tumor development, thereby preventing further cellular deterioration. Furthermore, the transcriptome analysis of immune cells in tumor tissue can be used to classify immune cells, their immune escape mechanisms and drug resistance mechanisms, and to develop effective clinical targeted therapies combined with immunotherapy. Moreover, this method enables the study of intercellular communication and the interaction of tumor cells and non-malignant cells to reveal their role in carcinogenesis. scRNA-seq provides new technical means for further development of tumor research and is expected to make significant breakthroughs in this field. This review focuses on the principles of scRNA-seq, with an emphasis on the application of scRNA-seq in tumor heterogeneity, pathogenesis, and treatment.

Download Full-text