MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway

Guan, Junhong; Lu, Changzheng; Jin, Qihuang; Lu, Haijun; Chen, Xiang; Tian, Lei; Zhang, Yanbin; Ortega, Janice; Zhang, Junqiu; Siteni, Silvia; Chen, Mingyi; Gu, Liya; Shay, Jerry W.; Davis, Anthony J.; Chen, Zhijian J.; Fu, Yang Xin; Li, Guo Min

doi:10.1016/j.ccell.2020.11.004

Cited by 147 publications

(101 citation statements)

References 57 publications

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“…In this group of diseases, and in familiar SLE, gDNA accumulates in the cytosol because of basal S-phase by-products generation or retroelement transposition. Prominent nuclear damage and genomic instability in cancer cells are further examples where the formation of micronuclei or mobilization of transposable genetic elements can feed the cytosol with DNA leading to cGAS activation and IFN-I production ( 62 , 63 ).…”

Section: Cgas-sting Signalingmentioning

confidence: 99%

“…WASp and Arp2/3 have been implicated in preserving genomic stability via homology-directed repair of DNA double-strand breaks (DSB) during replication stress and by counteracting nuclear deformation ( 87 , 88 ). On the other hand, genomic instability has been clearly linked to cGAS activation ( 63 ). It is thus reasonable to expect an interplay between perturbed actin dynamics, genomic stability, and cGAS activation.…”

Section: The Role Of Actin In Maintaining Compartmentalization Of Self-dnamentioning

confidence: 99%

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Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

2021

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Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA. Hence, understanding how cellular mechanism controls the pathogenic responses to self-nucleic acid has important clinical implications. Fine-tuned membrane trafficking and cellular compartmentalization are two major factors that balance activation of DNA sensors and availability of self-DNA ligands. Intracellular transport and organelle architecture are in turn regulated by cytoskeletal dynamics, yet the precise impact of actin remodeling on DNA sensing remains elusive. This review proposes a critical analysis of the established and hypothetical connections between self-DNA recognition and actin dynamics. As a paradigm of this concept, we discuss recent evidence of deregulated self-DNA sensing in the prototypical actin-related primary immune deficiency (Wiskott-Aldrich syndrome). We anticipate a broader impact of actin-dependent processes on tolerance to self-DNA in autoimmune disorders.

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Section: Cgas-sting Signalingmentioning

confidence: 99%

Section: The Role Of Actin In Maintaining Compartmentalization Of Self-dnamentioning

confidence: 99%

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

2021

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“…Notably, regardless of tumor type, the objective response rate to anti-PD-1 therapies in MSI-H tumors appears to peak at slightly above 50%, suggesting that nearly half of the tumors are intrinsically resistant. The genomic and immunologic explanations for the variable response in GC remain a significant knowledge gap though recent studies have highlighted the importance of DNA sensing and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation, which could trigger anti-tumor innate immune response elements (14,(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer

et al. 2021

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Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progressionfree survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1 + CD8 + T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.Research.

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“…Specifically, Lu and colleagues elegantly showed that in CRC and breast cancer models with defects in MMR, cytosolic DNA is accumulated and triggers a CD8+ T cell specific response. At the same time, Guan and colleagues disclosed that MLH1 regulates exonuclease 1 (EXO1) nuclease activity, and the impairment of the MLH1–EXO1 interaction leads to replication protein A (RPA) exhaustion and consequently DNA breaks and the release of nuclear DNA into the cytoplasm [ 117 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

Amodio

Mauri

Reilly

et al. 2021

Cancers

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Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.

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MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway

Cited by 147 publications

References 57 publications

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

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