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Tumor-Induced L-Selectin^high Suppressor T Cells Mediate Potent Effector T Cell Blockade and Cause Failure of Otherwise Curative Adoptive Immunotherapy¹

Liaomin Peng^*, Jørgen Kjaergäard^*, Gregory E. Plautz^*, Mohamed Awad^*, Judith A. Drazba, Suyu Shu^* and Peter A. Cohen^2,*

^* Center for Surgery Research, Cleveland Clinic Foundation, and Lerner Research Institute, Cleveland, OH 44195

Tumor-specific effector T cells (T_E) are naturally sensitized within the L-selectin^low (CD62L^low) fraction of tumor-draining lymph nodes (TDLN). Whether isolated from day 9 (D9) or day 12 (D12) TDLN, 5 million L-selectin^low T_E could be culture activated and adoptively transferred to achieve complete rejection of established intradermal, pulmonary, and brain tumors. Surprisingly, although 25 million unfractionated T cells from D9 TDLN were equally effective, even 100 million unfractionated T cells from D12 TDLN seldom prevented lethal intradermal tumor progression, despite a pronounced therapeutic excess of T_E. This highly reproducible treatment failure was due to cotransfer of tumor-induced, L-selectin^high suppressor T cells (T_S) which were also present in D12 TDLN. In contrast, D9 TDLN and normal spleens lacked L-selectin^high T_S. Only those L-selectin^high D12 TDLN T cells that down-regulated L-selectin during culture activation were suppressive in vivo and in vitro, and, like L-selectin^low T_E, trafficked promptly into tumors following i.v. administration. This is the first demonstration that adoptive immunotherapy can fail as a direct result of passenger T_S that share certain phenotypic and trafficking features of T_E, even when otherwise curative doses of T_E have been administered. Furthermore, in contrast to recently described CD4⁺CD25⁺ T_S and plasmacytoid dendritic cell-activated T_S, tumor-induced L-selectin^high T_S prevent tumor rejection via blockade of sensitized, activated T_E rather than via afferent blockade.

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