Tumor-Induced L-Selectinhigh Suppressor T Cells Mediate Potent Effector T Cell Blockade and Cause Failure of Otherwise Curative Adoptive Immunotherapy

Abstract

Tumor-specific effector T cells (TE) are naturally sensitized within the L-selectinlow (CD62Llow) fraction of tumor-draining lymph nodes (TDLN). Whether isolated from day 9 (D9) or day 12 (D12) TDLN, 5 million L-selectinlow TE 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 TE. This highly reproducible treatment failure was due to cotransfer of tumor-induced, L-selectinhigh suppressor T cells (TS) which were also present in D12 TDLN. In contrast, D9 TDLN and normal spleens lacked L-selectinhigh TS. Only those L-selectinhigh D12 TDLN T cells that down-regulated L-selectin during culture activation were suppressive in vivo and in vitro, and, like L-selectinlow TE, trafficked promptly into tumors following i.v. administration. This is the first demonstration that adoptive immunotherapy can fail as a direct result of passenger TS that share certain phenotypic and trafficking features of TE, even when otherwise curative doses of TE have been administered. Furthermore, in contrast to recently described CD4+CD25+ TS and plasmacytoid dendritic cell-activated TS, tumor-induced L-selectinhigh TS prevent tumor rejection via blockade of sensitized, activated TE rather than via afferent blockade.