Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment.

Abstract

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.

• Authors: Graham Thomas, Luca Micci, Wenjing Yang, Joseph Katakowski, Cecilia Oderup, Purnima Sundar, Xiao Wang, Kenneth G Geles, Shobha Potluri, Shahram Salek-Ardakani
• Journal: Frontiers in oncology (Front Oncol) Vol. 11 Pg. 711673 ( 2021) ISSN: 2234-943X [Print] Switzerland
• PMID: 34381732 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Thomas, Micci, Yang, Katakowski, Oderup, Sundar, Wang, Geles, Potluri and Salek-Ardakani.