Toll-like receptor agonist therapy can profoundly augment the antitumor activity of adoptively transferred CD8(+) T cells without host preconditioning

Journal for Immunotherapy of Cancer
Michelle H NelsonChrystal M Paulos

Abstract

Lymphodepletion enhances adoptive T cell transfer (ACT) therapy by activating the innate immune system via microbes released from the radiation-injured gut. Microbial components, such as LPS, are key mediators of total body irradiation (TBI) enhancement, but our ability to strategically use these toll-like receptor (TLR) agonists to bolster the potency of T cell-based therapies for cancer remains elusive. Herein, we used TLR4 agonist LPS as a tool to address how and when to use TLR agonists to effectively improve cancer immunotherapy. To determine the mechanisms of how innate immune activation via lymphodepletion potentiated antitumor T cell immunity, we utilized the pmel-1 melanoma mouse model. B16F10-bearing mice were preconditioned with 5Gy TBI and given a tripartite ACT therapy (consisting of transferred pmel-1 CD8(+) T cells, vaccination with fowlpox encoding gp100, and IL-2) along with TLR4 agonist LPS. The timing of LPS administration and the requirement of individual components of the tripartite therapy were evaluated based on tumor growth and the phenotype of recovered splenocytes by flow cytometry. We also evaluated the role of non-toxic and clinically used TLR4 and TLR9 agonists-monophosphoryl lipid A (MPL) and CpG O...Continue Reading

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Citations

Jul 10, 2016·Cancer Microenvironment : Official Journal of the International Cancer Microenvironment Society·Didier MeseureIvan Bieche
Nov 18, 2017·Oncoimmunology·Carole FournierLionel Apetoh
May 26, 2017·Cancer·Erez Nissim BaruchGal Markel
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Nov 6, 2018·Trends in Immunology·Alexandria P CogdillJennifer A Wargo

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Methods Mentioned

BETA
lymphodepletion
flow cytometry
transgenic

Software Mentioned

FlowJo

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