Central memory self/tumor-reactive CD8 + T cells confer superior antitumor immunity compared with effector memory T cells

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Abstract
Central memory CD8 + T cells (T CM ) and effector memory CD8 + T cells (T EM ) are found in humans and mice; however, their relative contributions to host immunity have only recently been examined in vivo . Further, the ability of T CM to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD8 + T cell memory subsets, we used an established model for the in vitro generation of T CM and T EM by using IL-15 and IL-2, respectively. Adoptively transferred T CM exhibited a potent in vivo recall response when combined with tumor-antigen vaccination and exogenous IL-2, leading to the eradication of large established tumors. By contrast, T EM were far less effective on a per-cell basis. Microarray analysis revealed that the signature of highly in vivo effective antitumor T cells included the overexpression of genes responsible for trafficking to secondary lymphoid tissues. This gene expression profile correctly predicted the in vitro and in vivo lymphoid-homing attributes of tumor-reactive T cells. Furthermore, we found that homing to secondary lymphoid tissue is required for optimal tumor treatment. Our findings indicated that highly in vivo effective antitumor T cells were those that initially targeted secondary lymphoid tissue, rather than tumor sites, as had previously been postulated. Thus, tumor-reactive CD8 + T cell populations with the phenotypic and functional attributes of T CM may be superior to T EM /effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination.