Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity

Christian S Hinrichs, Zachary A Borman, Lydie Cassard, Luca Gattinoni, Rosanne Spolski, Zhiya Yu, Luis Sanchez-Perez, Pawel Muranski, Steven J Kern, Carol Logun, Douglas C Palmer, Yun Ji, Robert N Reger, Warren J Leonard, Robert L Danner, Steven A Rosenberg, Nicholas P Restifo
Proceedings of the National Academy of Sciences of the United States of America 2009 October 13, 106 (41): 17469-74
Effector cells derived from central memory CD8(+) T cells were reported to engraft and survive better than those derived from effector memory populations, suggesting that they are superior for use in adoptive immunotherapy studies. However, previous studies did not evaluate the relative efficacy of effector cells derived from naïve T cells. We sought to investigate the efficacy of tumor-specific effector cells derived from naïve or central memory T-cell subsets using transgenic or retrovirally transduced T cells engineered to express a tumor-specific T-cell receptor. We found that naïve, rather than central memory T cells, gave rise to an effector population that mediated superior antitumor immunity upon adoptive transfer. Effector cells developed from naïve T cells lost the expression of CD62L more rapidly than those derived from central memory T cells, but did not acquire the expression of KLRG-1, a marker for terminal differentiation and replicative senescence. Consistent with this KLRG-1(-) phenotype, naïve-derived cells were capable of a greater proliferative burst and had enhanced cytokine production after adoptive transfer. These results indicate that insertion of genes that confer antitumor specificity into naïve rather than central memory CD8(+) T cells may allow superior efficacy upon adoptive transfer.

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