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Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific cd8(+) t cells

Academic Article
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Overview

authors

  • Gattinoni, L.
  • Finkelstein, S. E.
  • Klebanoff, C. A.
  • Antony, P. A.
  • Palmer, D. C.
  • Spiess, P. J.
  • Hwang, L. N.
  • Yu, Z. Y.
  • Wrzesinski, C.
  • Heimann, D. M.
  • Surh, Charles
  • Rosenberg, S. A.
  • Restifo, N. P.

publication date

  • October 2005

journal

  • Journal of Experimental Medicine  Journal

abstract

  • Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The gammaC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of gammaC cytokine-responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

subject areas

  • Adoptive Transfer
  • Animals
  • Autoimmunity
  • CD8-Positive T-Lymphocytes
  • Cell Line, Tumor
  • Cytokines
  • Female
  • Lymphopenia
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms
  • T-Lymphocytes, Regulatory
  • Vaccination
  • Whole-Body Irradiation
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Identity

PubMed Central ID

  • PMC1397916

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20050732

PubMed ID

  • 16203864
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Additional Document Info

start page

  • 907

end page

  • 912

volume

  • 202

issue

  • 7

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