Selective reactivation of STING signaling to target Merkel cell carcinoma

Abstract

<jats:p>Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STING<jats:sup>S162A/G230I/Q266I</jats:sup>, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered to MCC cells via an AAV vector. Introducing STING<jats:sup>S162A/G230I/Q266I</jats:sup>expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) show increased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STING<jats:sup>S162A/G230I/Q266I</jats:sup>causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STING<jats:sup>S162A/G230I/Q266I</jats:sup>in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.</jats:p>

Human Cancer Cells Sense Cytosolic Nucleic Acids Through the RIG-I–MAVS Pathway and cGAS–STING Pathway

“…Several experimental studies have reported the expression of cGAS and/or STING in human melanoma, colorectal cancer, Merkel cell carcinoma, and ovarian cancer ( Xia et al, 2016a , b ; de Queiroz et al, 2019 ; Liu et al, 2020 ). However, their expression in other human cancer cells remains unknown.…”

Merkel Cell Polyomavirus and Merkel Cell Carcinoma

“…STING protein was undetectable in VP MKL-1, MKL-2 and MS-1 cells, but not in non-classical VN MCC13, MCC26 and UISO cells. Five MCC tumors (virus state not mentioned) also stained negative with STING antibodies [ 215 ]. STING silencing may help MCC tumor cells to escape immune eradication.…”

“…Whether VN- and VP-MCC patients display different sensitivity to radiation is not known, but a previous study had shown that absence of STING impaired radiation-mediated tumor regression [ 220 ]. Because it was recently reported that STING expression is downregulated in VP-MCC cells [ 215 ], VP-MCC may be less sensitive to radiotherapy than VN-MCC.…”

“…Thus, ADAM 10 and 17 inhibitors may stimulate the immune system and could be used for the treatment of VP-MCC. VP-MCC cell lines and MCC tumors do not express STING (see Section 4 ; [ 215 ]). Treating MKL-1 and MS-1 cells that stably express STING responsive to the STING agonist DMXAA not only restored the induction of interferons and proinflammatory cytokines and chemokines, but stimulated PD-L1 expression, T cell migration and activation, and triggered cell death in vitro [ 215 ].…”

“…VP-MCC cell lines and MCC tumors do not express STING (see Section 4 ; [ 215 ]). Treating MKL-1 and MS-1 cells that stably express STING responsive to the STING agonist DMXAA not only restored the induction of interferons and proinflammatory cytokines and chemokines, but stimulated PD-L1 expression, T cell migration and activation, and triggered cell death in vitro [ 215 ]. The authors suggested that introducing STING by e.g., an adenovirus-based vector in MCC together with DMXAA could be used to treat VP-MCC patients.…”