Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy
Christopher A. Klebanoff, … , Richard M. Siegel, Nicholas P. Restifo
Christopher A. Klebanoff, … , Richard M. Siegel, Nicholas P. Restifo
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):318-334. https://doi.org/10.1172/JCI81217.
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Research Article Immunology Oncology

Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Abstract

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies.

Authors

Christopher A. Klebanoff, Christopher D. Scott, Anthony J. Leonardi, Tori N. Yamamoto, Anthony C. Cruz, Claudia Ouyang, Madhu Ramaswamy, Rahul Roychoudhuri, Yun Ji, Robert L. Eil, Madhusudhanan Sukumar, Joseph G. Crompton, Douglas C. Palmer, Zachary A. Borman, David Clever, Stacy K. Thomas, Shashankkumar Patel, Zhiya Yu, Pawel Muranski, Hui Liu, Ena Wang, Francesco M. Marincola, Alena Gros, Luca Gattinoni, Steven A. Rosenberg, Richard M. Siegel, Nicholas P. Restifo

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Figure 5

FasL-Fas interactions mediate precocious differentiation.

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FasL-Fas interactions mediate precocious differentiation. (A) Representa...
(A) Representative FACS plots, (B) summary bar graph, and (C) scatter plot demonstrating T cell subset frequencies or percentage of IFN-γ+CD8+ T cells 6 days following priming of Ly5.1+ TN alone or in a 1:1 mixture with Ly5.2+ TMem with CD3/CD28-specific antibodies, IL-2, and a blocking antibody against FasL (αFasL) or isotype (IgG) control. (D) FACS analysis and (E) bar graph summarizing the distribution of CD8+ T cell subsets 6 days following priming of Ly5.2+ WT TN pmel-1 (TNWT/WT) or lpr/lpr TN pmel-1 (TNlpr/lpr) cells alone or in the presence of a 1:1 mixture with WT Ly5.1+ TMem. All results shown as mean ± SEM with n = 2–3 per indicated condition or cell type. Statistical comparisons performed using an unpaired 2-tailed Student’s t test corrected for multiple comparisons by a Bonferroni adjustment. *P < 0.05; **P < 0.01; ***P < 0.001. Data shown are representative of 14 (A and B), 4 (C), and 3 (D and E) independently performed experiments.