Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.
Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.
Hinrichs
Christian S
CS
National Cancer Institute, Bethesda, MD, USA.
Borman
Zachary A
ZA
Gattinoni
Luca
L
Yu
Zhiya
Z
Burns
William R
WR
Huang
Jianping
J
Klebanoff
Christopher A
CA
Johnson
Laura A
LA
Kerkar
Sid P
SP
Yang
Shicheng
S
Muranski
Pawel
P
Palmer
Douglas C
DC
Scott
Christopher D
CD
Morgan
Richard A
RA
Robbins
Paul F
PF
Rosenberg
Steven A
SA
Restifo
Nicholas P
NP
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D016615:Telomere / Q000235:genetics; D014161:Transduction, Genetic; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
D016207:Cytokines; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7