Immunotherapy with STING and TLR9 agonists promotes synergistic therapeutic efficacy with suppressed cancer-associated fibroblasts in colon carcinoma

Sare Hajiabadi; Soodeh Alidadi; Zohreh Montakhab Farahi; Mohammad M Ghahramani Seno; Hamidreza Farzin; Alireza Haghparast

doi:10.3389/fimmu.2023.1258691

Immunotherapy with STING and TLR9 agonists promotes synergistic therapeutic efficacy with suppressed cancer-associated fibroblasts in colon carcinoma

Front Immunol. 2023 Oct 13:14:1258691. doi: 10.3389/fimmu.2023.1258691. eCollection 2023.

Authors

Sare Hajiabadi¹, Soodeh Alidadi¹, Zohreh Montakhab Farahi¹, Mohammad M Ghahramani Seno², Hamidreza Farzin³, Alireza Haghparast¹

Affiliations

¹ Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.
² Program for Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
³ Razi Vaccine and Serum Research Institute, Agriculture Research, Education and Extension Organization (AREEO), Mashhad, Iran.

Abstract

The innate immune sensing of nucleic acids using effective immunoadjuvants is critical for increasing protective immune responses against cancer. Stimulators of interferon genes (STING) and toll-like receptor 9 (TLR9) agonists are considered promising candidates in several preclinical tumor models with the potential to be used in clinical settings. However, the effects of such treatment on tumor stroma are currently unknown. In this study, we investigated the immunotherapeutic effects of ADU-S100 as a STING agonist and CpG ODN1826 as a TLR9 agonist in a preclinical model of colon carcinoma. Tumor-bearing mice were treated intratumorally on days 10 and 16 post-tumor inoculation with ADU-S100 and CpG ODN1826. Cytokine profiles in the tumor and spleen, tumor cell apoptosis, the infiltration of immune cells, and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) were evaluated to identify the immunological mechanisms after treatment. The powerful antitumor activity of single and combination treatments, the upregulation of the expression of pro-inflammatory cytokines in the tumor and spleen, and the recruitment and infiltration of the TME by immune cells revealed the synergism of immunoadjuvants in the eradication of the colon carcinoma model. Remarkably, the significant downregulation of CAFs in the TME indicated that suppression of tumorigenesis occurred after immunoadjuvant therapy. The results illustrate the potential of targeting the STING and TLR9 pathways as powerful immunoadjuvants in the treatment of preclinical colon carcinoma and the possibility of harnessing these pathways in future therapeutic approaches.

Keywords: CAFs; STING; TLR9; colon carcinoma; immunoadjuvants.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic / pharmacology
Adjuvants, Immunologic / therapeutic use
Animals
Cancer-Associated Fibroblasts* / metabolism
Carcinoma*
Colonic Neoplasms* / therapy
Immunotherapy
Mice
Toll-Like Receptor 9 / agonists
Tumor Microenvironment

Substances

Adjuvants, Immunologic
ADU-S100
Toll-Like Receptor 9
Sting1 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research described in this article. This study was partially supported by grant number 46013 from the Ferdowsi University of Mashhad to AH. Financial support was also received from the Iranian Biotechnology Initiative Council.