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

Cell Rep. 2018 Dec 11;25(11):3074-3085.e5. doi: 10.1016/j.celrep.2018.11.047.


Intratumoral (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-induced anti-tumor immunity.

Keywords: ADU-S100; CD8(+) T cell; ImmunoOncology; STING; abscopal immunity; anti-tumor immunity; checkpoint inhibitor; cyclic dinucleotide; intratumoral; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen / metabolism
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Dose-Response Relationship, Immunologic
  • Drug Resistance, Neoplasm
  • Hematopoiesis
  • Immunity*
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / metabolism
  • S100 Proteins / administration & dosage
  • S100 Proteins / immunology


  • CTLA-4 Antigen
  • Cytokines
  • Membrane Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • S100 Proteins
  • Sting1 protein, mouse