Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity

Publication date: 11 December 2018Source: Cell Reports, Volume 25, Issue 11Author(s): Kelsey E. Sivick, Anthony L. Desbien, Laura Hix Glickman, Gabrielle L. Reiner, Leticia Corrales, Natalie H. Surh, Thomas E. Hudson, Uyen T. Vu, Brian J. Francica, Tamara Banda, George E. Katibah, David B. Kanne, Justin J. Leong, Ken Metchette, Jacob R. Bruml, Chudi O. Ndubaku, Jeffrey M. McKenna, Yan Feng, Lianxing Zheng, Steven L. BenderSummaryIntratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-indu...
Source: Cell Reports - Category: Cytology Source Type: research