Editors' ChoiceCancer

A T cell memory problem?

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Science Translational Medicine  20 Jan 2016:
Vol. 8, Issue 322, pp. 322ec10
DOI: 10.1126/scitranslmed.aaf0859

Despite multiple preclinical models showing that adoptive cell transfer (ACT) of less differentiated T cells results in superior in vivo expansion, persistence, and antitumor capacity compared with highly differentiated T cell subsets, most human studies still use unfractionated T cell populations. This practice is largely based on the assumption that the mere representation of at least some undifferentiated subsets in the population used to generate therapeutic T cells is sufficient to preserve antitumor immunity.

Klebanoff et al. challenge this view, using both human and mouse cells and present evidence that antigen-experienced CD8+ T cells (TMem) have the capacity to induce precocious differentiation of naïve T cells (TN), both during cell expansion ex vivo and after adoptive cotransfer in vivo, through a previously unrecognized direct T cell–T cell interaction. The predominant outcome of TMem-induced differentiation was a marked dose-dependent attrition of the highly potent and less differentiated T stem cell memory (TSCM) and T central memory (TCM) populations and an accumulation of T effector memory (TEM) cells, resulting in impaired proliferation, cellular persistence, and antitumor efficacy of adoptively transferred TN-derived cells in B16 melanoma mouse models. Mechanistically, the phenomenon was found to be dependent on activation and cell contact and mediated by nonapoptotic Fas signaling, resulting in activation of Akt and ribosomal S6 protein (S6) kinases responsible for cellular differentiation and metabolism. Although further studies are needed to resolve the precise signaling cascade necessary for Fas-induced precocious differentiation, the authors show that FasL was both necessary and sufficient to induce the phenomenon. Induction of Fas signaling in the absence of TMem cells enhanced differentiation and impaired antitumor immunity, whereas isolation of TN cells before priming and Fas signaling blockade prevented TMem-induced differentiation and preserved the antitumor efficacy of naïve cells within mixed populations. These findings suggest that more differentiated T cell subsets have the capacity to synchronize their differentiation state with less differentiated subsets in a process similar to quorum sensing in unicellular organisms, and that disruption of this collectivist behavior could enhance the efficacy of T cell-based adoptive immunotherapies.

The recent progress in the engineering of T lymphocytes and the ability to reliably confer tumor antigen reactivity with high efficiency has greatly simplified the generation of therapeutic T cells of any memory subset. In this study, Klebanoff and colleagues raise important questions regarding the optimal source, expansion, and quality of therapeutic T cells used for transfer. Strategies that either separate younger and older T cell subsets before cell expansion or disrupt the younger cells’ capacity to respond to TMem cell–mediated signaling by antagonizing Fas or Akt signaling may ultimately enhance the efficacy of adoptive immunotherapies.

C. A. Klebanoff et al., Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318–334 (2016). [Full Text]

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