IL-2 Expression Defines Melanoma-Specific, Self-Renewing T Cells

Although adoptive T-cell transfer has shown some clinical efficacy in metastatic melanoma, the ability of ex vivo–expanded human T cells to persist long term after transfer is limiting. In an effort to improve adoptive immunotherapy, Wang and colleagues sought to prospectively identify tumor-specific central memory T (T_CM) cells, a population of CD8-positive T cells shown to have self-renewal potential, enhanced survival, and antitumor activity in animal models. Peripheral blood cultures from patients with metastatic melanoma were screened based on the relative production of interleukin-2 (IL-2) and IFN-γ in response to antigen; cells defined by a high IL-2:IFN ratio index were confirmed to be tumor-specific T_CM cells based on expression of the surface marker CD62L, indicating that the stoichiometric ratio of these cytokines was correlated with the memory T-cell phenotype. Functional analysis of these high-index cells showed maintenance of antigen specificity and enhanced proliferative capacity in vitro, which resulted in significantly greater expansion and augmented response to exogenous IL-2 and suggested that T_CM cells may have increased survival in vivo. To test this possibility, tumor-specific effector T-cell clones derived from the high-index T_CM cells of 5 patients with metastatic melanoma were expanded and adoptively transferred back into their hosts. These cells persisted long term in 4 patients and targeted skin melanocytes in all 5 patients, and a small subset of these clones regained a T_CM phenotype and the ability to produce IL-2. Therefore, these results define an effective, high-throughput method to distinguish T_CM cells with durable engraftment potential. However, because only a minimal effect on tumor growth was observed, this study supports the combination of adoptive transfer of high IL-2:IFN–index cells with adjuvant therapies, such as inhibition of the negative regulators CTLA-4 and PD-1, to improve clinical benefit.

Wang A, Chandran S, Shah SA, Chiu Y, Paria BC, Aghamolla T, et al. The stoichiometric production of IL-2 and IFN-γ mRNA defines memory T cells that can self-renew after adoptive transfer in humans. Sci Transl Med 2012;4:149ra120.

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