TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors. Academic Article uri icon

Overview

abstract

  • The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422-33. ©2018 AACR.

publication date

  • February 22, 2018

Research

keywords

  • Antineoplastic Agents
  • Membrane Proteins
  • Neoplasms
  • Nucleotides, Cyclic
  • Radiation Tolerance
  • Stromal Cells
  • Tumor Necrosis Factor-alpha

Identity

PubMed Central ID

  • PMC6215542

Scopus Document Identifier

  • 85048093266

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-17-0263

PubMed ID

  • 29472271

Additional Document Info

volume

  • 6

issue

  • 4