Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy?

Abstract

CD8(+) T cells have been described as being naive or one of 4 antigen (Ag)-experienced subtypes representing a continuum of differentiation and maturation: T memory stem cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cells. In mice, adoptive cell transfer of less-differentiated naive T cells, T memory stem cell, and central memory T cell subsets have consistently demonstrated superior in vivo expansion, persistence, and antitumor capacities relative to the more differentiated effector memory T cell and effector T cell subsets. Retrospective analyses from human adoptive cell transfer trials have confirmed that transfer of less-differentiated T-cell subsets is highly correlated with objective clinical responses. These findings, combined with the recent ability to convey de novo Ag reactivity with high efficiency through genetic engineering of exogenous T-cell or chimeric Ag receptors, now challenge the field with 3 important questions: (1) how should less-differentiated T-cell subsets be isolated for human clinical trials?; (2) what is the best means of expanding T cells ex vivo in such a way as to not corrupt the beneficial traits of the younger subsets?; and (3) is it necessary to physically separate younger subsets from their more differentiated counterparts? Answering these questions will allow for the rational development of the next generation of highly effective and potentially curative T-cell therapies for the treatment of cancer.

Figure 1. Re-iterative progress in enhancing the efficacy of adoptive CD8⁺ T cell therapy for the treatment of melanoma using the pmel-1 mouse model

The use of alternative γ_c cytokines or less differentiated T cell subsets has resulted in progressive improvements in the therapeutic efficacy of tumor-reactive CD8⁺ T cells, thus providing for effective tumor destruction with the transfer of limited numbers of cells. IL, interleukin; T_SCM, T memory stem cell.

Figure 2. A timeline of progress in the understanding of T cell qualities associated with effective adoptive immunotherapies for the treatment of cancer in mice and humans

ACT, adoptive cell transfer; T_SCM, T memory stem cell; T_CM, T central memory; T_EM, T effector memory; T_EFF, T effector cell; γ_c, common γ-chain receptor; CML, chronic myelogenous leukemia; TCR, T cell receptor; APC, antigen presenting cell.

Figure 3. Clinical strategies to isolate specific T cell subsets for adoptive cell transfer

Peripheral blood lymphocytes can be sorted in specific T cell subsets by employing diverse strategies, including functional isolation by PCR-based screening (left panel), magnetic bead isolation (center panel) and flow cytometric cell-sorting (right panel). Each technique has relative benefits and limitation in terms of cell purity and yield, complexity of the parameters used for isolation, labor and cost which are represented as low (+), intermediate (++) or high (+++).