TLR5 Agonists Enhance Anti-Tumor Immunity and Overcome Resistance to Immune Checkpoint Therapy

Authors

Caleb Gonzalez
Sarah Williamson
Seth T Gammon
Sarah Glazer
Joon Haeng Rhee
David Piwnica-Worms

Publication Date

1-12-2023

Journal

Communications Biology

Abstract

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF and CXCL5 (as well as high IL-15) were candidate predictive biomarkers correlating with enhanced survival. CBLB502-induced enhancement of ICT was also observed in poorly immunogenic B16-F10 melanoma tumors. Combination immune checkpoint therapy plus TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors.

Keywords

Animals, Mice, Adaptive Immunity, Cytokines, Flagellin, Melanoma, Experimental, Toll-Like Receptor 5

Comments

Supplementary Materials

Data Availability Statement

PMID: 36635337