PD-L1 sustains chronic, cancer cell–intrinsic responses to type I interferon, enhancing resistance to DNA damage

2021 ◽  
Vol 118 (47) ◽  
pp. e2112258118
Author(s):  
HyeonJoo Cheon ◽  
Elise G. Holvey-Bates ◽  
Daniel J. McGrail ◽  
George R. Stark
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Type I Interferon ◽  
Critical Role ◽  
Constitutive Expression ◽  
Type I ◽  
Independent Manner ◽  
Low Level ◽  
Acute Response ◽  
Independent Functions

Programmed death ligand 1 (PD-L1), an immune-checkpoint protein expressed on cancer cells, also functions independently of the immune system. We found that PD-L1 inhibits the killing of cancer cells in response to DNA damage in an immune-independent manner by suppressing their acute response to type I interferon (IFN; IFN-I). In addition, PD-L1 plays a critical role in sustaining high levels of constitutive expression in cancer cells of a subset of IFN-induced genes, the IFN-related DNA damage resistance signature (IRDS) which, paradoxically, protects cancer cells. The cyclic GMP-AMP synthase-stimulator of the IFN genes (cGAS-STING) pathway is constitutively activated in a subset of cancer cells in the presence of high levels of PD-L1, thus leading to a constitutive, low level of IFN-β expression, which in turn increases IRDS expression. The constitutive low level of IFN-β expression is critical for the survival of cancer cells addicted to self-produced IFN-β. Our study reveals immune-independent functions of PD-L1 that inhibit cytotoxic acute responses to IFN-I and promote protective IRDS expression by supporting protective chronic IFN-I responses, both of which enhance the resistance of cancer cells to DNA damage.

TREX1 is a checkpoint for innate immune sensing of DNA damage that fosters cancer immune resistance

2017 ◽  
Vol 1 (5) ◽  
pp. 509-515
Author(s):  
Sandra Demaria ◽  
Claire Vanpouille-Box
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Cancer Progression ◽  
Type I ◽  
Replicative Stress ◽  
Immune Resistance ◽  
Cytoplasmic Dna ◽  
Autoimmune Pathology

Genomic instability is a hallmark of neoplastic transformation that leads to the accumulation of mutations, and generates a state of replicative stress in neoplastic cells associated with dysregulated DNA damage repair (DDR) responses. The importance of increasing mutations in driving cancer progression is well established, whereas relatively little attention has been devoted to the DNA displaced to the cytosol of cancer cells, a byproduct of genomic instability and of the ensuing DDR response. The presence of DNA in the cytosol promotes the activation of viral defense pathways in all cells, leading to activation of innate and adaptive immune responses. In fact, the improper accumulation of cytosolic DNA in normal cells is known to drive severe autoimmune pathology. Thus, cancer cells must evade cytoplasmic DNA detection pathways to avoid immune-mediated destruction. The main sensor for cytoplasmic DNA is the cyclic GMP–AMP synthase, cGAS. Upon activation by cytosolic DNA, cGAS catalyzes the formation of the second messenger cGAMP, which activates STING (stimulator of IFN genes), leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated antiviral and antitumor immunity, and its production by cancer cells can be subverted by several mechanisms. However, the key upstream regulator of cytosolic DNA-mediated immune stimulation is the DNA exonuclease 3′-repair exonuclease 1 (TREX1). Here, we will discuss evidence in support of a role of TREX1 as an immune checkpoint that, when up-regulated, hinders the development of antitumor immune responses.

Abstract B05: Induction of DNA damage in high-grade serous carcinoma induces type I interferon signaling

2020 ◽  
Author(s):  
Danielle E. Bolland ◽  
Yuning Hao ◽  
Yee Sun Tan ◽  
Jake Reske ◽  
Lijun Tan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Type I Interferon ◽  
Serous Carcinoma ◽  
Type I ◽  
High Grade ◽  
Interferon Signaling

scholarly journals Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2450
Author(s):  
Aneta Gandalovičová ◽  
Anna-Marie Šůchová ◽  
Vladimír Čermák ◽  
Ladislav Merta ◽  
Daniel Rösel ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Type I Interferon ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Melanoma Cells ◽  
Interferon Response ◽  
Type I ◽  
Expression Of Genes ◽  
Interferon Signalling ◽  
Inflammatory Signalling

The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. Here, we report that cells after mesenchymal–amoeboid transition show the increased expression of genes associated with the type I interferon response. Moreover, the sustained activation of type I interferon signalling in response to IFNβ mediated by the Stat1/Stat2/IRF9 complex enhances the round amoeboid phenotype in melanoma cells, whereas its downregulation by various approaches promotes the mesenchymal invasive phenotype. Overall, we demonstrate that interferon signalling is associated with the amoeboid phenotype of cancer cells and suggest a novel role of IFNβ in promoting cancer invasion plasticity, aside from its known role as a tumour suppressor.

scholarly journals Zerumbone increases oxidative stress in a thiol‐dependent ROS ‐independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation

2014 ◽  
Vol 4 (2) ◽  
pp. 278-292 ◽  
Author(s):  
Amit Deorukhkar ◽  
Niharika Ahuja ◽  
Armando‐Lopez Mercado ◽  
Parmeswaran Diagaradjane ◽  
Uma Raju ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Independent Manner ◽  
Colorectal Cancer Cells

scholarly journals NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

2009 ◽  
Vol 5 (7) ◽  
pp. e1000500 ◽  
Author(s):  
Amit K. Pandey ◽  
Yibin Yang ◽  
Zhaozhao Jiang ◽  
Sarah M. Fortune ◽  
Francois Coulombe ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type I Interferon ◽  
Critical Role ◽  
Interferon Response ◽  
Type I

scholarly journals Induction of DNA Damage in Ovarian Cancer Induces Type I Interferon Signaling

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Danielle E. Bolland ◽  
Yee Sun Tan ◽  
Yuning Hao ◽  
Kari E. Hacker ◽  
Lijun Tan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling

scholarly journals The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses

2010 ◽  
Vol 84 (16) ◽  
pp. 8051-8061 ◽  
Author(s):  
Xiaobo Lei ◽  
Xinlei Liu ◽  
Yijie Ma ◽  
Zhenmin Sun ◽  
Yaowu Yang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Type I Interferon ◽  
Critical Role ◽  
Enterovirus 71 ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Retinoid Acid ◽  
Inducible Gene

ABSTRACT Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease and fatal neurological diseases. Immature or impaired immunity is thought to associate with increased morbidity and mortality. In a murine model, EV71 does not facilitate the production of type I interferon (IFN) that plays a critical role in the first-line defense against viral infection. Administration of a neutralizing antibody to IFN-α/β exacerbates the virus-induced disease. However, the molecular events governing this process remain elusive. Here, we report that EV71 suppresses the induction of antiviral immunity by targeting the cytosolic receptor retinoid acid-inducible gene I (RIG-I). In infected cells, EV71 inhibits the expression of IFN-β, IFN-stimulated gene 54 (ISG54), ISG56, and tumor necrosis factor alpha. Among structural and nonstructural proteins encoded by EV71, the 3C protein is capable of inhibiting IFN-β activation by virus and RIG-I. Nevertheless, EV71 3C exhibits no inhibitory activity on MDA5. Remarkably, when expressed in mammalian cells, EV71 3C associates with RIG-I via the caspase recruitment domain. This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect. An H40D substitution is detrimental, but the protease activity associated with 3C is dispensable. Together, these results suggest that inhibition of RIG-I-mediated type I IFN responses by the 3C protein may contribute to the pathogenesis of EV71 infection.

scholarly journals RIG-I Detects Kaposi’s Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Yugen Zhang ◽  
Dirk P. Dittmer ◽  
Piotr A. Mieczkowski ◽  
Kurtis M. Host ◽  
William G. Fusco ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Type I Interferon ◽  
Kaposi’S Sarcoma ◽  
Innate Immune ◽  
Type I ◽  
Independent Manner ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Pol Iii ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Inducible Gene

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the innate immune response against many RNA viruses. We previously showed that RIG-I restricts Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (J. A. West et al., J Virol 88:5778–5787, 2014, https://doi.org/10.1128/JVI.03226-13). In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses. Knockdown or inhibition of RNA Pol III had no effect on beta interferon (IFN-β) induction by KSHV. By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF810420-10496, Repeat region (LIR1)119059-119204, and ORF2543561-43650. The sequence dissimilarity between these fragments suggests that RIG-I detects a particular structure rather than a specific sequence motif. Synthesized ORF810420-10496 RNA stimulated RIG-I-dependent but RNA Pol III-independent IFN-β signaling. In summary, several KSHV RNAs are sensed by RIG-I in a RNA Pol III-independent manner. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Innate immune responses against viral infections, especially the induction of type I interferon, are critical for limiting the replication of viruses. Retinoic acid-inducible gene I (RIG-I), a cytosolic RNA helicase sensor, plays a significant role in the induction of type I interferon responses following viral infection. Here, we identified multiple RNA regions in KSHV as potential virus ligands that bind to RIG-I and stimulate RIG-I-dependent but RNA Pol III-independent IFN-β signaling. Our results expand the role of RIG-I by providing an example of a DNA virus activating a canonical RNA-sensing pathway.

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