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 Therapeutics

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 6

Precocious differentiation is mediated by nonapoptotic Fas signaling.

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Precocious differentiation is mediated by nonapoptotic Fas signaling. (A...
(A) Representative FACS plots and (B) bar graph summarizing the distribution of T cell subsets and IFN-γ production in isolated TN cells primed with CD3/CD28-specific antibodies, IL-2, and indicated doses of lz-FasL for 6 days prior to analysis. Data shown are based on n = 3 independently maintained cultures/condition. (C) Relative overall cell yield and (D) relative cell yield of TEM or IFN-γ+ cells, normalized to no lz-FasL treatment, of TN-derived cells grown in the presence of titrated amounts of lz-FasL (C) or 33 ng/ml lz-FasL (D); data shown in C and D are based on n = 3–6 and n = 3 independently maintained cultures/condition, respectively. (E) Specific cell death of activated CD8+ T cells derived from WT (WT/WT), Lpr (lpr/lpr), and FasC194Vlpr/lpr mice following exposure to titrated amounts of lz-FasL or a vehicle control; n = 11 per condition/cell type. (F) Representative FACS plots demonstrating the frequency of TN-derived cell subsets and (G) bar graph demonstrating fold increase in TEM phenotype cells after WT/WT, lpr/lpr, or FasC194Vlpr/lpr CD8+ T cells were expanded with CD3/CD28-specific antibodies and IL-2 alone or with 40 ng/ml of lz-FasL for 6 days; n = 6–9 independently maintained cultures/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. Results are representative of 6 (A), 2 (C–E), and 4 (F and G) independently performed experiments and are displayed as mean ± SEM.