Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion

Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8 T cells for treatment, they also cause decline in the cell's therapeutic...

Full description

Saved in:
Bibliographic Details
Published in:JCI insight 2017-03, Vol.2 (5), p.e90772-e90772
Main Authors: Bowers, Jacob S, Nelson, Michelle H, Majchrzak, Kinga, Bailey, Stefanie R, Rohrer, Baerbel, Kaiser, Andrew Dm, Atkinson, Carl, Gattinoni, Luca, Paulos, Chrystal M
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cellular Senescence
Humans
Immunologic Memory
Immunotherapy, Adoptive
Lung Neoplasms - immunology
Lung Neoplasms - therapy
Melanoma, Experimental - immunology
Melanoma, Experimental - therapy
Mesothelioma - immunology
Mesothelioma - therapy
Mesothelioma, Malignant
Mice
Mice, Inbred C57BL
Th17 Cells - cytology
Th17 Cells - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8 T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4 T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR ) Th17 cells also retained their ability to regress human mesothelioma, while CAR Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.90772