cGAS is essential for the antitumor effect of immune checkpoint blockade

Wang, Hua; Hu, Shuiqing; Chen, Xiang; Shi, Heping; Chen, Chuo; Sun, Lijun; Chen, Zhijian J.

doi:10.1073/pnas.1621363114

Cited by 453 publications

(394 citation statements)

References 31 publications

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“…However, it will be very interesting to test whether cGAS deletion promotes tumor development driven by oncogenes such as Ras, which is known to induce senescence. In this context, we recently reported that cGas-deficient mice are refractory to the antitumor effect of immune checkpoint blockade in a syngeneic tumor transplant model (42), indicating that cGAS is required for generating intrinsic antitumor immunity. It remains to be determined whether cGAS has a cellautonomous function in impeding the transformation of a normal cell into a cancer cell.…”

Section: Discussionmentioning

confidence: 99%

“…This observation suggests that senescence may act as a barrier to tumor progression. Our findings that cGAS is required for senescence and our previous findings that cGAS is important for antitumor immunity predict that cGAS may be a tumor suppressor under some circumstances (42). To test this possibility, we carried out bioinformatics analyses of publicly available gene expression datasets, including The (human) Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the Cancer Biomedical Informatics Grid (caBIG).…”

Section: Low Expression Of Cgas Is Correlated With Poor Survival Outcmentioning

confidence: 99%

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cGAS is essential for cellular senescence

Yang

Wang

Ren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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783

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Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.ellular senescence is a state of irreversible cell cycle arrest triggered by various types of cellular and environmental stress, such as telomere shortening, oncogene activation, and DNA damage (1, 2). Senescence appears to be an antiproliferation process that limits the growth of damaged cells and acts as a potent barrier to tumorigenesis (3, 4). Senescence is characterized by several unique features, including enlarged and flattened cell morphology (5), increased senescence-associated β-galactosidase (SA-β-Gal) activity (6, 7), and in some cell types, a widespread change in chromatin modification, known as senescence-associated heterochromatin foci (SAHF) (7). At the molecular level, the p53-p21 WAF1 and pRb-p16 INK4a tumor suppressor pathways have been reported to be key mechanisms that control the execution and maintenance of senescence (8,9). In addition to these cellular features, senescent cells also undergo massive changes in the expression of genes that are thought to affect the tissue microenvironment (5). Senescent cells secrete a variety of soluble factors including inflammatory cytokines, growth factors, and proteases; such senescence-associated secretory phenotype (SASP) is a hallmark of senescence (10-12).Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13). Interleukin 6 (IL6) and IL8, two key components of SASP, reinforce the senescence growth arrest in neighboring cells (14,15). Additionally, these cytokines and other secreted factors attract immune cells, leading to the elimination of senescent cells (16). Given these important functions, SASP is regulated at both transcriptional and epigenetic levels, such as by nuclear factor κB (NF...

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Section: Discussionmentioning

confidence: 99%

Section: Low Expression Of Cgas Is Correlated With Poor Survival Outcmentioning

confidence: 99%

cGAS is essential for cellular senescence

Yang

Wang

Ren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

783

733

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“…Moreover, many patients suffer severe adverse effects, especially when treatments are combined (37). Recently, endogenous IFN was shown to be involved in immune checkpoint blockade efficacy (11)(12)(13)38). Anti-PDL1 sdAb therapy added to the tumor stasis effect of Clec9A-mAFN in the B16 tumor model (Fig.…”

Section: Complete and Safe Tumor Eradication By Dc-targeted Afn In Comentioning

confidence: 99%

“…Several host immune cells, including dendritic cells (DC), T and B lymphocytes, natural killer (NK) cells, and macrophages, all respond to IFN and may be involved in antitumor activity (2,5). Furthermore, endogenous IFN is essential for cancer immunosurveillance (6,7), and for anticancer therapies including chemotherapy, radiotherapy, immunotherapies, and checkpoint inhibition (5,(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments

et al. 2018

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An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I IFN has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1,000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon (AFN)-targeting Clec9Aþ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AFNs provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker. Significance: Targeted type I interferon elicits powerful antitumor efficacy, similar to wild-type IFN, but without any toxic side effects. Cancer Res; 78(2); 463-74. Ó2017 AACR.

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“…Mice deficient in IFN-I signaling display enhanced susceptibility to tumor formation [38 • ], and IFN-I signaling is critical for the development of anti-tumor activity of NK cells [39 • ] as well as antigen cross-priming of tumor-specific CD8+ T cells by DC [40 • ,41 • ]. Among an array innate immune signaling molecules examined for an essential role in tumor growth and immunogenicity, STING and cGAS appear to be uniquely indispensable for natural or spontaneous anti-tumor immunity [42 •• ,43 •• ], as well as the immunogenic effects of irradiation [44 •• ], CD47 blockade [45], and immune checkpoint therapy [46]. Accordingly, cGAMP is a potent anti-tumor agent against many solid and suspension tumor types [47–50].…”

Section: Cancer Cancer Therapy and Genotoxic Stressmentioning

confidence: 99%

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Dhanwani

Takahashi

Sharma

2018

Current Opinion in Immunology

100

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In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.

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cGAS is essential for the antitumor effect of immune checkpoint blockade

Cited by 453 publications

References 31 publications

cGAS is essential for cellular senescence

cGAS is essential for cellular senescence

Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

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