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 Article has an altmetric score of 28

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 2

TMem cause precocious differentiation of naive cells.

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TMem cause precocious differentiation of naive cells. (A) Representative...
(A) Representative FACS and (B) bar graph summarizing the distribution of Ly5.1+CD8+ TN-derived cell subsets 6 days following priming with CD3/CD28-specific antibodies and IL-2 alone or with Ly5.2+CD8+ TMem cells. Data shown after gating on Ly5.1+CD8+cells. (C) qPCR analysis of Sell, Ccr7, and Cd27 expression in FACS-sorted reisolated TN cells primed alone, TN cells primed with TMem cells, or TMem cells primed alone. (D) Granzyme B and (E) IFN-γ intracellular staining in TN-derived cells stimulated with PMA/ionomycin following expansion alone or with TMem cells. (F) IFN-γ ELISA of supernatants from reisolated TN-derived cells expanded alone or with TMem cells 6 days prior to overnight stimulation with hgp10025–33 peptide. (G) Heat maps of differentially expressed genes (1-way ANOVA, pFDR < 5%) among TN-derived cells expanded alone or with TMem cells at 18 and 96 hours. (H) RMA-normalized intensity of selected TN-associated genes. (I) Expression of effector cell–associated factors assessed by qPCR at 96 hours from FACS reisolated TN-derived progeny expanded with or without TMem cells or TMem cells expanded alone. (J) In vivo expansion and (K) tumor regression following i.v. adoptive transfer of TN-derived progeny expanded alone or with TMem cells, or TMem cells grown alone in combination with 6 Gy irradiation, i.v. rVV-hgp100, and 3 days of i.p. IL-2. n = 3 independently maintained cultures/condition or time point for experiments shown in B, C, and F–I. K was performed with n = 5 mice per group. All results shown as mean ± SEM. Statistical comparisons performed using an unpaired 2-tailed Student’s t test corrected for multiple comparisons by Bonferroni adjustment. *P < 0.05; **P < 0.01. Data are representative of 16 (A and B), 3 (D and E), and 2 (C, F, and I–K) independent experiments.