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TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy
Medicine and HealthCommunications Biology

TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy

C. Gonzalez, S. Williamson, et al.

This groundbreaking study by Caleb Gonzalez, Sarah Williamson, Seth T. Gammon, Sarah Glazer, Joon Haeng Rhee, and David Piwinca-Worms explores how TLR5 agonists like flagellin and CBLB502 can significantly enhance survival rates when combined with immune checkpoint inhibitors against tough cancer types, such as triple-negative breast cancer and melanoma. The findings reveal promising new strategies to tackle cancer resistance and build long-term immunological memory.... show more
GeneralSummaryMetrics
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 survival 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.
Publisher
Communications Biology
Published On
Jan 12, 2023
Authors
Caleb Gonzalez, Sarah Williamson, Seth T. Gammon, Sarah Glazer, Joon Haeng Rhee, David Piwinca-Worms
DOI
https://doi.org/10.1038/s42003-022-04403-8
Tags
TLR5 agonistsimmune checkpoint inhibitorstriple-negative breast cancermelanomasurvival ratescytokine profilesimmunological memory
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