Open AccessA kinetic investigation of interacting, stimulated T cells identifies conditions for rapid functional enhancement, minimal phenotype differentiation, and improved adoptive cell transfer tumor eradication
Author(s) -
Jing Zhou,
Michael T. Bethune,
Natalia V. Malkova,
Alexander M. Sutherland,
Begoñya Comin-Anduix,
Yapeng Su,
David Baltimore,
Antoni Ribas,
James R. Heath
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0191634
Subject(s) - priming (agriculture) , adoptive cell transfer , microbiology and biotechnology , cd8 , phenotype , t cell , cytolysis , cytotoxic t cell , stimulation , effector , cell , biology , cellular differentiation , cell therapy , chemistry , immunology , immune system , in vitro , stem cell , biochemistry , neuroscience , botany , germination , gene
For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differentiation, and response to stimulation hinders the co-optimization of these factors. We report on a biophysical investigation of how the short-term kinetics of T cell functional activation, through molecular stimulation and cell-cell interactions, competes with phenotype differentiation. T cells receive molecular stimulation for a few minutes to a few hours in bulk culture. Following this priming period, the cells are then analyzed at the transcriptional level, or isolated as single cells, with continuing molecular stimulation, within microchambers for analysis via 11-plex secreted protein assays. We resolve a rapid feedback mechanism, promoted by T cell—T cell contact interactions, which strongly amplifies T cell functional performance while yielding only minimal phenotype differentiation. When tested in mouse models of ACT, optimally primed T cells lead to complete tumor eradication. A similar kinetic process is identified in CD8 + and CD4 + T cells collected from a patient with metastatic melanoma.