Selective reactivation of STING signaling to target Merkel cell carcinoma
Menée in vitro, cette étude met en évidence l'intérêt de réactiver sélectivement la voie de signalisation de la protéine STING pour traiter un carcinome à cellules de Merkel
The immune-dampened status of Merkel cell carcinoma (MCC) tumors presents a major obstacle to developing effective immunotherapies. We propose that STING silencing may cause the immunologically “cold” MCC tumor microenvironments by blocking cytokine production and, consequently, impeding cytotoxic T cell infiltration, activation, and killing of tumor cells. Our findings indicate that targeted activation of STINGS162A/G230I/Q266I by DMXAA could be a viable strategy for bolstering antitumor adaptive immunity in STING-silenced cancers. DMXAA does not stimulate human STING activity. Therefore, when combined with AAV delivery of STINGS162A/G230I/Q266I to primary tumors, it may achieve tumor-specific STING activation without concomitant pathology caused by systemic inflammation frequently observed with traditional human STING agonists. This approach could synergize with existing immune-checkpoint therapies to improve MCC treatment.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, STINGS162A/G230I/Q266I, 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 STINGS162A/G230I/Q266I 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 STINGS162A/G230I/Q266I 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 STINGS162A/G230I/Q266I in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.