Manuel Adrian Suter
Email Address
lsimasu@nus.edu.sg
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Publication cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells(Nature Research, 2021-03-31) Suter, Manuel Adrian; Tan, Nikki Y.; Thiam, Chung Hwee; Khatoo, Muznah; MacAry, Paul A.; Angeli, Veronique; Gasser, Stephan; Zhang, Y. L.; MICROBIOLOGY AND IMMUNOLOGY; LIFE SCIENCES INSTITUTEDeficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells. Inhibition of IL-6 or the downstream JAK2/STAT3 signaling restored responsiveness to STING agonists in DU145 cells. STING activity in murine TRAMP-C2 prostate cancer cells was critical for tumor rejection and immune cell infiltration. Endogenous STING agonists including double-stranded DNA and RNA:DNA hybrids present in TRAMP-C2 cells contribute to tumor rejection, but tumor growth was further suppressed by administration of cGAMP. Intratumoral co-injections of IL-6 significantly reduced the anti-tumor effects of cGAMP. In summary, STING in tumor cells contributes to tumor rejection in prostate cancer cells, but its functions are frequently suppressed in tumor cells in part via JAK2 and STAT3 pathways. © 2021, The Author(s).Publication TCR-like antibodies mediate complement and antibody-dependent cellular cytotoxicity against Epstein-Barr virus-transformed B lymphoblastoid cells expressing different HLA-A?02 microvariants(2017) Lai J.; Choo J.A.L.; Tan W.J.; Too C.T.; Oo M.Z.; Suter M.A.; Mustafa F.B.; Srinivasan N.; Chan C.E.Z.; Lim A.G.X.; Zhong Y.; Chan S.H.; Hanson B.J.; Gascoigne N.R.J.; MacAry P.A.; MEDICINE; SURGERY; MICROBIOLOGY AND IMMUNOLOGY; LIFE SCIENCES INSTITUTE; PAEDIATRICSEpstein-Barr virus (EBV) is a common gammaherpesvirus associated with various human malignancies. Antibodies with T cell receptor-like specificities (TCR-like mAbs) provide a means to target intracellular tumor-or virus-associated antigens by recognising their processed peptides presented on major histocompatibility complex (MHC) class I (pMHC) complexes. These antibodies are however thought to be relevant only for a single HLA allele. Here, we show that HLA-A?02:01-restricted EBV antigenic peptides EBNA1562-570, LMP1125-133 and LMP2A426-434 display binding degeneracy towards HLA-A?02 allelic microvariants, and that these pMHC complexes are recognised by anti-EBV TCR-like mAbs E1, L1 and L2 raised in the context of HLA-A?02:01. These antibodies bound endogenously derived pMHC targets on EBV-transformed human B lymphoblastoid cell lines expressing A?02:01, A?02:03, A?02:06 and A?02:07 alleles. More importantly, these TCR-like mAbs mediated both complement-dependent and antibody-dependent cellular cytotoxicity of these cell lines in vitro. This finding suggests the utility of TCR-like mAbs against target cells of closely related HLA subtypes, and the potential applicability of similar reagents within populations of diverse HLA-A?02 alleles. © 2017 The Author(s).Publication Tumoral STING is required for effective anticancer immunity(AMER ASSOC CANCER RESEARCH, 2019-02-01) Suter, Manuel Adrian; Zhang, Wendy Ya Ling; Khatoo, Muznah Bte Nazar Khan; Tan, Nikki Ya Ling; Too, Chien Tei; Tripathi, Shubhita; MacAry, Paul A; Angeli, Veronique; Gasser, Stephan; Assoc Prof Paul A MacAry; MICROBIOLOGY AND IMMUNOLOGY; LIFE SCIENCES INSTITUTEAbstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that catalyses the synthesis of cGAMP, which serves as a ligand for stimulator of interferon (IFN) genes (STING). Activation of STING results in production of type I IFNs through phosphorylation of TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3). Type I IFNs are critical participants in the innate and adaptive immune recognition of cancer cells. Deficiencies in the cGAS-STING signalling pathway have been reported in many tumors. This mitigates expression of type I IFNs and may thus contribute to non-inflamed tumor microenvironment. In particular, a non-T-cell-inflamed tumor microenvironment correlates with poor patient survival. STING agonists may contribute to antitumor activity by upregulating proinflammatory cytokines and type I IFNs and various STING agonists are now being tested in clinical trials. The role of STING in immune cells is relatively well understood; however, its role in tumor cells has not yet been described in detail. Here we show that cGAS is able to bind to DNA present in the cytosol of tumor cells and subsequently induces STING signaling leading to expression of type I IFNs. Knockout of STING in mouse prostate TRAMP-C2 tumor cells resulted in higher tumor burden and reduced infiltration of immune cells such as dendritic and CD8+ T-cells into the tumor microenvironment. Consistently, treatment with the STING agonist cGAMP elevated type I IFNs levels in TRAMP-C2 cells and led to a reduced tumor volume compared to untreated control. This suggests a pivotal role of tumoral STING in antitumor immunity. However, despite intact STING expression, most tested human cancer cell lines were not responsive to various STING agonists and consequently failed to upregulate expression of type I IFNs. In contrast, all tested tumor cell lines responded to Poly(I:C)-induced TLR3 signaling, suggesting that failure to respond to cGAMP was due to a defect upstream of TBK1. Downregulation of cGAS did not render cells responsive to cGAMP, indicating that inability to respond to cGAMP is due to deficiencies of STING to activate TBK1. In the human and mouse prostate cancer cell lines DU145 and TRAMP-C2, respectively, autocrine IL-6 rendered cells unresponsive to STING agonists. While treatment with anti-IL-6 antibodies restored cGAMP responsiveness in DU145 cells, addition of recombinant IL-6 suppressed cGAMP-mediated upregulation of type I IFNs. In summary, our data suggest that cytosolic DNA activates the cGAS-STING signaling pathway. A functional STING is pivotal for eliciting an effective anticancer immune response. In most human cancer cell lines, however, STING signalling is inhibited. Since STING agonists are being evaluated in clinical trials, it is crucial to understand mechanisms that mediate STING unresponsiveness. We show that in tested prostate cancer cells, IL-6 signals contribute to unresponsiveness of STING and blocking of IL-6 can restore responsiveness towards STING agonists. Citation Format: Manuel Adrian Suter, Wendy Ya Ling Zhang, Muznah Bte Nazar Khan Khatoo, Nikki Ya Ling Tan, Chien Tei Too, Shubhita Tripathi, Paul A. MacAry, Veronique Angeli, Stephan Gasser. Tumoral STING is required for effective anticancer immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B189.