scholarly journals Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tian-Yu Song ◽  
Min Long ◽  
Hai-Xin Zhao ◽  
Miao-Wen Zou ◽  
Hong-Jie Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Human Cancer ◽  
Mirna Biogenesis ◽  
Cytokine Signaling ◽  
Tumor Evolution ◽  
Mouse Tumor ◽  
The Core ◽  
The Impact

AbstractCancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy.

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Wnt Effector TCF4 Is Dispensable for Wnt Signaling in Human Cancer Cells

Genes ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 439 ◽  
Author(s):  
Dusan Hrckulak ◽  
Lucie Janeckova ◽  
Lucie Lanikova ◽  
Vitezslav Kriz ◽  
Monika Horazna ◽  
...  
Keyword(s):  
T Cell ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Human Cancer ◽  
Wnt Signaling Pathway ◽  
Human Cells ◽  
Cellular Systems ◽  
Mouse Tissue ◽  
T Cell Factor ◽  
Human Cancer Cells

T-cell factor 4 (TCF4), together with β-catenin coactivator, functions as the major transcriptional mediator of the canonical wingless/integrated (Wnt) signaling pathway in the intestinal epithelium. The pathway activity is essential for both intestinal homeostasis and tumorigenesis. To date, several mouse models and cellular systems have been used to analyze TCF4 function. However, some findings were conflicting, especially those that were related to the defects observed in the mouse gastrointestinal tract after Tcf4 gene deletion, or to a potential tumor suppressive role of the gene in intestinal cancer cells or tumors. Here, we present the results obtained using a newly generated conditional Tcf4 allele that allows inactivation of all potential Tcf4 isoforms in the mouse tissue or small intestinal and colon organoids. We also employed the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to disrupt the TCF4 gene in human cells. We showed that in adult mice, epithelial expression of Tcf4 is indispensable for cell proliferation and tumor initiation. However, in human cells, the TCF4 role is redundant with the related T-cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) transcription factors.

Dendritic cells fused with human cancer cells: morphology, antigen expression, and T cell stimulation

2004 ◽  
Vol 113 (3) ◽  
pp. 261-269 ◽  
Author(s):  
Shigeo Koido ◽  
Masaya Ohana ◽  
Chunlei Liu ◽  
Najmosama Nikrui ◽  
John Durfee ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Human Cancer ◽  
Antigen Expression ◽  
Cell Stimulation ◽  
Human Cancer Cells ◽  
T Cell Stimulation

scholarly journals The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1161 ◽  
Author(s):  
Magdalena Cal ◽  
Irwin Matyjaszczyk ◽  
Ireneusz Litwin ◽  
Daria Augustyniak ◽  
Rafał Ogórek ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Reactive Oxygen ◽  
Atp Depletion ◽  
Mitochondrial Enzymes ◽  
Oxygen Species ◽  
Human Cancer Cells ◽  
The Impact

3-bromopyruvate (3-BP) is a small molecule with anticancer and antimicrobial activities. 3-BP is taken up selectively by cancer cells’ mono-carboxylate transporters (MCTs), which are highly overexpressed by many cancers. When 3-BP enters cancer cells it inactivates several glycolytic and mitochondrial enzymes, leading to ATP depletion and the generation of reactive oxygen species. While mechanisms of 3-BP uptake and its influence on cell metabolism are well understood, the impact of 3-BP at certain concentrations on DNA integrity has never been investigated in detail. Here we have collected several lines of evidence suggesting that 3-BP induces DNA damage probably as a result of ROS generation, in both yeast and human cancer cells, when its concentration is sufficiently low and most cells are still viable. We also demonstrate that in yeast 3-BP treatment leads to generation of DNA double-strand breaks only in S-phase of the cell cycle, possibly as a result of oxidative DNA damage. This leads to DNA damage, checkpoint activation and focal accumulation of the DNA response proteins. Interestingly, in human cancer cells exposure to 3-BP also induces DNA breaks that trigger H2A.X phosphorylation. Our current data shed new light on the mechanisms by which a sufficiently low concentration of 3-BP can induce cytotoxicity at the DNA level, a finding that might be important for the future design of anticancer therapies.

scholarly journals Simulated microgravity-mediated reversion of murine lymphoma immune evasion

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jillian H. Bradley ◽  
Shannon Barwick ◽  
Gillian Q. Horn ◽  
Elizabeth Ullrich ◽  
Brianna Best ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Simulated Microgravity ◽  
Cancer Therapeutics ◽  
T Cell Response ◽  
Tumor Escape ◽  
Murine Lymphoma ◽  
Static Conditions

Abstract No human has returned to the moon since the end of the Apollo program 47 years ago, however, new missions are planned for an orbital outpost. Space radiation and the potential for cancer remain as important issues to the future of human space exploration. While improved shield technologies and protective biologicals are under development, little is known concerning the interaction between cancer cells and host immunity in microgravity. As a hallmark of cancer, tumor cells employ mechanisms of immune evasion to avoid elimination by protective CD4+ and CD8+ T cells. We showed that a murine lymphoma was able to produce a soluble factor that inhibited the function of dendritic cells in activating the CD4+ T cells. Culture of the lymphoma cells in simulated microgravity (SMG), and not Static conditions, restored the CD4+ T cell response and augmented CD8+ T cell-mediated destruction of the cancer cells in vitro and in vivo. Thus, SMG impaired the mechanism of tumor escape and rendered the cancer cells more susceptible to T cell-mediated elimination. The stress of microgravity may expose the most critical components of a tumor’s escape mechanism for astronaut protection and the generation of new cancer therapeutics for patients on Earth.

Enhancement of antiproliferative activity by phototautomerization of anthrylphenols

2015 ◽  
Vol 14 (6) ◽  
pp. 1082-1092 ◽  
Author(s):  
Marijeta Kralj ◽  
Lidija Uzelac ◽  
Yu-Hsuan Wang ◽  
Peter Wan ◽  
Martina Tireli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Quinone Methide ◽  
Cellular Proteins ◽  
Human Cancer Cells ◽  
The Impact

9-(2-Hydroxyphenyl)anthracene (1) moderately inhibited the proliferation of human cancer cells, but irradiation considerably enhanced the effect due to the formation of quinone methide. The effect is not only due to the damage of DNA, but also due to the impact on the cellular proteins.

scholarly journals Different Lineages of P1A-Expressing Cancer Cells Use Divergent Modes of Immune Evasion for T-Cell Adoptive Therapy

2006 ◽  
Vol 66 (16) ◽  
pp. 8241-8249 ◽  
Author(s):  
Xue-Feng Bai ◽  
Jin-Qing Liu ◽  
Pramod S. Joshi ◽  
Lizhong Wang ◽  
Lijie Yin ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Adoptive Therapy

scholarly journals PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity

2017 ◽  
Vol 214 (4) ◽  
pp. 895-904 ◽  
Author(s):  
Vikram R. Juneja ◽  
Kathleen A. McGuire ◽  
Robert T. Manguso ◽  
Martin W. LaFleur ◽  
Natalie Collins ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Antitumor Immunity ◽  
Cd8 T Cell ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.

scholarly journals THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy

2021 ◽  
Vol 9 (8) ◽  
pp. e002443
Author(s):  
Chushu Li ◽  
Hao Chi ◽  
Shouyan Deng ◽  
Huanbin Wang ◽  
Han Yao ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Tissue Microarrays ◽  
Mouse Tumor ◽  
Tissue Samples ◽  
Cargo Protein ◽  
Promising Target

BackgroundThe abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.MethodsCombined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.ResultsTHADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.ConclusionsOur data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.

Sign in / Sign up

Export Citation Format

Share Document