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

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 & 7 others Ena Wang, Francesco M. Marincola, Alena Gros, Luca Gattinoni, Steven A. Rosenberg, Richard M. Siegel, Nicholas P. Restifo

Research output: Contribution to journalArticle

73 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)318-334
Number of pages17
JournalJournal of Clinical Investigation
Volume126
Issue number1
DOIs
Publication statusPublished - 4 Jan 2016

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Adoptive Immunotherapy
Cell Differentiation
T-Lymphocytes
Adoptive Transfer
T-Lymphocyte Subsets
Population
Immunity
Quorum Sensing
Cell Communication
Immunotherapy
Stem Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Klebanoff, C. A., Scott, C. D., Leonardi, A. J., Yamamoto, T. N., Cruz, A. C., Ouyang, C., ... Restifo, N. P. (2016). Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. Journal of Clinical Investigation, 126(1), 318-334. https://doi.org/10.1172/JCI81217

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

In: Journal of Clinical Investigation, Vol. 126, No. 1, 04.01.2016, p. 318-334.

Research output: Contribution to journalArticle

Klebanoff, CA, Scott, CD, Leonardi, AJ, Yamamoto, TN, Cruz, AC, Ouyang, C, Ramaswamy, M, Roychoudhuri, R, Ji, Y, Eil, RL, Sukumar, M, Crompton, JG, Palmer, DC, Borman, ZA, Clever, D, Thomas, SK, Patel, S, Yu, Z, Muranski, P, Liu, H, Wang, E, Marincola, FM, Gros, A, Gattinoni, L, Rosenberg, SA, Siegel, RM & Restifo, NP 2016, 'Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy', Journal of Clinical Investigation, vol. 126, no. 1, pp. 318-334. https://doi.org/10.1172/JCI81217
Klebanoff CA, Scott CD, Leonardi AJ, Yamamoto TN, Cruz AC, Ouyang C et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. Journal of Clinical Investigation. 2016 Jan 4;126(1):318-334. https://doi.org/10.1172/JCI81217
Klebanoff, Christopher A. ; Scott, Christopher D. ; Leonardi, Anthony J. ; Yamamoto, Tori N. ; Cruz, Anthony C. ; Ouyang, Claudia ; Ramaswamy, Madhu ; Roychoudhuri, Rahul ; Ji, Yun ; Eil, Robert L. ; Sukumar, Madhusudhanan ; Crompton, Joseph G. ; Palmer, Douglas C. ; Borman, Zachary A. ; Clever, David ; Thomas, Stacy K. ; Patel, Shashankkumar ; Yu, Zhiya ; Muranski, Pawel ; Liu, Hui ; Wang, Ena ; Marincola, Francesco M. ; Gros, Alena ; Gattinoni, Luca ; Rosenberg, Steven A. ; Siegel, Richard M. ; Restifo, Nicholas P. / Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 1. pp. 318-334.
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AU - Roychoudhuri, Rahul

AU - Ji, Yun

AU - Eil, Robert L.

AU - Sukumar, Madhusudhanan

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