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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-07, Vol.102 (27), p.9571-9576
• Main Authors: Klebanoff, Christopher A, Gattinoni, Luca, Torabi-Parizi, Parizad, Kerstann, Keith, Cardones, Adela R, Finkelstein, Steven E, Palmer, Douglas C, Antony, Paul A, Hwang, Sam T, Rosenberg, Steven A, Waldmann, Thomas A, Restifo, Nicholas P
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490

Central memory CD8 super(+) T cells (T sub(CM)) and effector memory CD8 super(+) T cells (T sub(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 sub(CM) to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD8 super(+) T cell memory subsets, we used an established model for the in vitro generation of T sub(CM) and T sub(EM) by using IL-15 and IL-2, respectively. Adoptively transferred T sub(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 sub(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 super(+) T cell populations with the phenotypic and functional attributes of T sub(CM) may be superior to T sub(EM)/effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination.