Editors' ChoiceHuman Immunology

Refreshing Your Memory

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Science Translational Medicine  26 Oct 2011:
Vol. 3, Issue 106, pp. 106ec175
DOI: 10.1126/scitranslmed.3003340

Therapeutic cancer vaccines are one of the most promising treatments in development for potentially devastating cancers such as metastatic melanoma. In several studies, cancer vaccines have been shown to effectively expand and activate a patient’s CD8+ T cells; these cytotoxic immune cells then seek out and destroy tumor cells. One of the major challenges to this approach, however, is that the tumor-specific T cells induced are prone to immunological exhaustion and senescence, which causes these cells to no longer attack the tumor and hampers their long-term effectiveness. Now, Gattinoni et al. make substantial progress in resolving this issue by identifying a memory stem cell–like population in humans that may provide a durable antitumor response.

Gattinoni et al. previously reported in mice that activating the Wnt–β-catenin pathway in T cells generated a population of T memory stem cells (TSCM cells) that had the ability to self-renew and could differentiate into two memory cell types: central memory (TCM cells) and effector memory T cells (TEM cells). In the current study, they sought to identify this same cell subset in humans using a similar approach. The resulting population of cells expressed several surface markers characteristic of naïve T cells but also expressed two conventional memory cell surface markers, CD95 and interleukin-2Rβ (IL-2Rβ). The authors used these two markers to identify a putative TSCM cell population from the peripheral blood of human donors; these cells were phenotypically similar to TSCM identified in mice. The human TSCM cells functioned similarly to conventional memory cells as well—rapidly responding and expanding extensively after activation. The genetic signature of these TSCM cells was suggestive of a memory cell subset yet indicative of a less differentiated stem cell-like memory population. Indeed, TSCM cells had stem cell-like properties: They not only generated diverse progeny, but a portion of these cells remained undivided and retained the TSCM cell phenotype.

Finally, Gattinoni et al. showed that TSCM cells engrafted better than did TCM and TEM cells after transfer into highly immunodeficient mice, which suggests an improved replicative and survival capacity of this population. Importantly, these cells were also the most effective at triggering tumor regression in a mouse xenograft model. These exciting findings provide strong evidence for the existence of T memory stem cells and will likely spur studies that try and manipulate this population not only in the fight against cancer, but also in the development of vaccines to combat the spread of infectious disease.

L. Gattinoni et al., A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011). [PubMed]

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