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 3

TMem cells cause precocious differentiation of TN cells in vivo.

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TMem cells cause precocious differentiation of TN cells in vivo. (A) Exp...
(A) Experimental schema showing the generation, isolation, and transfer of Thy1.1+ pmel-1 TN cells (CD44loCD62L+) alone or in combination with FACS-sorted, vaccine-induced Ly5.1+ pmel-1 TMem cells (CD44hi) into Ly5.2+ hosts. (B) In vivo expansion and persistence of 1 × 105 adoptively transferred Thy1.1+ TN cells injected alone or in combination with 3 × 105 Ly5.1+ TMem cells into Ly5.2+ WT mice bearing 10-day established B16 melanomas. (C) FACS analysis on day 17 of CD27 and KLRG1 expression on CD8+Thy1.1+ TN-derived or CD8+Ly5.1+ TMem-derived cells. (D) Tumor regression and survival of mice bearing 10-day established B16 melanoma tumors who received 1 × 105 TN cells alone, in combination with 3 × 105 TMem cells, or 3 × 105 TMem cells alone. All treated mice received 6 Gy irradiation, i.v. rVV-gp100, and 3 days of i.p. IL-2. n = 3 mice/group/time point (B and C) or n = 5 mice per group (D). Results are displayed as mean ± SEM with statistical comparisons performed using an unpaired 2-tailed Student’s t test corrected for multiple comparisons by a Bonferroni adjustment or log-rank test for animal survival. *P < 0.05; **P < 0.01. Data shown are representative of 2 independently performed experiments.