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Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment

Straetemans, Trudy, Berrevoets, Cor, Coccoris, Miriam, Treffers-Westerlaken, Elike, Wijers, Rebecca, Cole, David, Dardalhon, Valerie, Sewell, Andrew K., Taylor, Naomi, Verweij, Jaap and Debets, Reno 2015. Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment. Molecular Therapy 23 (2) , pp. 396-406. 10.1038/mt.2014.215

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Abstract

Clinical therapy with T cells shows promise for cancer patients, but is currently challenged by incomplete responses and tumor relapse. The exact mechanisms that contribute to tumor relapse remain largely unclear. Here, we treated mouse melanomas with T cell receptor-engineered T cells directed against a human peptide-major histocompatibility complex antigen in immune-competent mice. T cells resulted in significant tumor regression, which was followed by relapse in about 80–90% of mice. Molecular analysis revealed that relapsed tumors harbored nonmutated antigen genes, not silenced by promoter methylation, and functionally expressed surface antigen at levels equal to nontreated tumors. Relapsed tumors resisted a second in vivo T cell treatment, but regained sensitivity to T cell treatment upon retransplantation in mice. Notably, relapsed tumors demonstrated decreased levels of CD8 T cells and monocytes, which were substantiated by downregulated expression of chemoattractants and adhesion molecules. These observations were confirmed when using T cells specific for a less immunogenic, endogenous mouse melanoma antigen. We conclude that tumors, when exposed to T cell treatment, can relapse without loss of antigen and develop a milieu that evades recruitment of effector CD8 T cells. Our findings support the concept to target the tumor milieu to aid T cell therapy in limiting tumor relapse

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RM Therapeutics. Pharmacology
Publisher: Nature Publishing Group
ISSN: 1525-0016
Date of Acceptance: 25 October 2014
Last Modified: 14 Mar 2019 10:12
URI: http://orca.cf.ac.uk/id/eprint/74257

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