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 January 4, 2016; First 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 10

Fas signaling controls T cell differentiation and influences adoptive immunotherapy efficacy.

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Fas signaling controls T cell differentiation and influences adoptive im...
(A) Tumor regression and (B) animal survival of mice bearing 10-day established s.c. B16 melanomas treated with 2.5 × 105 TN-derived pmel-1 cells primed alone, with lz-FasL (50 ng/ml), or with TMem in the presence of αFasL or IgG control. Viable cells were isolated using a density separation media before infusion. All treated mice received 6 Gy irradiation prior to cell infusion in addition to i.v. rVV-gp100 and 3 days of i.p. IL-2. Tumor treatment experiments performed with n = 5 mice/group. TMix, TN cells primed with TMem cells in a 1:1 mixture. (C) Engraftment efficiency of Thy1.1+ TN-derived pmel-1 cells (3 × 105) primed alone or with lz-FasL 18 hours following i.v. adoptive transfer into nonirradiated Ly5.2+ hosts; n = 5 mice/group. (D) Correlation between the slope of tumor growth and CD62L expression at the time of cell transfer on TN-derived pmel-1 cells primed alone with either lz-FasL (50 ng/ml), vehicle control, or with TMem and either αFasL or IgG. Pooled results from 2 independently performed experiments displayed using n = 4–10 mice per condition. Statistical comparisons performed using an unpaired 2-tailed Student’s t test or log-rank test for animal survival. *P < 0.05. Data shown are representative of 2 independent experiments with results displayed as mean ± SEM.