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

Overview of attention for article published in Journal for Immunotherapy of Cancer, February 2016
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Title
Toll-like receptor agonist therapy can profoundly augment the antitumor activity of adoptively transferred CD8+ T cells without host preconditioning
Published in
Journal for Immunotherapy of Cancer, February 2016
DOI 10.1186/s40425-016-0110-8
Pubmed ID
Authors

Michelle H. Nelson, Jacob S. Bowers, Stefanie R. Bailey, Marshall A. Diven, Caroline W. Fugle, Andrew D. M. Kaiser, Claudia Wrzesinski, Bei Liu, Nicholas P. Restifo, Chrystal 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 Oligodeoxynucleotide (CpG ODN), respectively- for ACT therapy. Here we report that while exogenous administration of LPS was able to enhance adoptively transferred CD8(+) T cells' tumor destruction, LPS treatment alone did not replace individual components of the tripartite ACT regimen, or obviate TBI. Moreover, we found that sequentially administering LPS during or one day prior to ACT therapy compromised tumor regression. In contrast, administering LPS after ACT potentiated the antitumor effectiveness of the regimen, thereby supporting the expansion of transferred tumor-specific CD8(+) T cells over host CD4(+) T cells. We also found that non-toxic TLR agonists MPL and CpG potentiated the antitumor activity of infused CD8(+) T cells. Finally, TBI was no longer needed to regress tumors in mice who were depleted of host CD4(+) T cells, given a tripartite ACT regimen and then treated with low dose LPS. Collectively, our results identify how and when to administer TLR agonists to augment T cell-based immunotherapy in the absence or presence of host preconditioning for treatment of advanced malignancies. Our findings have clinical implications for the design of next generation immune-based therapies for patients with cancer.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 44 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Chile 1 2%
United States 1 2%
Unknown 42 95%

Demographic breakdown

Readers by professional status Count As %
Researcher 12 27%
Student > Ph. D. Student 11 25%
Student > Master 6 14%
Other 5 11%
Student > Bachelor 3 7%
Other 2 5%
Unknown 5 11%
Readers by discipline Count As %
Agricultural and Biological Sciences 13 30%
Immunology and Microbiology 6 14%
Biochemistry, Genetics and Molecular Biology 5 11%
Medicine and Dentistry 4 9%
Materials Science 2 5%
Other 5 11%
Unknown 9 20%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 February 2016.
All research outputs
#5,430,460
of 7,214,390 outputs
Outputs from Journal for Immunotherapy of Cancer
#215
of 261 outputs
Outputs of similar age
#198,439
of 283,780 outputs
Outputs of similar age from Journal for Immunotherapy of Cancer
#9
of 11 outputs
Altmetric has tracked 7,214,390 research outputs across all sources so far. This one is in the 13th percentile – i.e., 13% of other outputs scored the same or lower than it.
So far Altmetric has tracked 261 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 20.9. This one is in the 4th percentile – i.e., 4% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 283,780 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 16th percentile – i.e., 16% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 11 others from the same source and published within six weeks on either side of this one. This one is in the 9th percentile – i.e., 9% of its contemporaries scored the same or lower than it.