STING agonist and IDO inhibitor combination therapy inhibits tumor progression in murine models of colorectal cancer

Cell Immunol. 2021 Aug:366:104384. doi: 10.1016/j.cellimm.2021.104384. Epub 2021 May 23.

Abstract

Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in colorectal cancer (CRC). Stimulator of interferon genes (STING) is a novel potential target and STING agonists have shown potential anti-tumor efficacy. Combined therapy based on synergistic mechanism can overcome the resistance. However, STING agonists-based combination therapies are deficient. We designed different immunotherapy combinations, including STING agonist, indoleamine 2,3 dioxygenase (IDO) inhibitor and PD-1 blockade, with purpose of exploring which option can effectively inhibit CRC growth. To further explore the possible reasons of therapeutic effectiveness, we observed the combination therapy in C57BL/6Tmem173gt mice. Our findings demonstrated that STING agonist diABZI combined with IDO inhibitor 1-MT significantly inhibited tumor growth, even better than the three-drug combination, promoted the recruitment of CD8+ T cells and dendritic cells, and decreased the infiltration of myeloid-derived suppressor cells. We conclude that diABZI combined with 1-MT is a promising option for CRC.

Keywords: 3 Dioxygenase (IDO); Colorectal cancer (CRC); Combination immunotherapy; Indoleamine 2; PD-1 blockade; Stimulator of interferon genes (STING).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use*
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / drug therapy*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy / methods*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Membrane Proteins / agonists*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / immunology*
  • Neoplasm Transplantation
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Tryptophan / pharmacology
  • Tryptophan / therapeutic use*

Substances

  • 1-methyl-L-tryptophan
  • Benzimidazoles
  • Immune Checkpoint Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Membrane Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Sting1 protein, mouse
  • Tryptophan