The T cells of many
cancer patients are naturally sensitized to
tumor-associated
antigens (Ag), or they can readily be sensitized with
vaccine maneuvers. In
melanoma patients, the adoptive transfer of such T cells can often be causally linked to the objective regression of established
tumors. So far, few patients have shown sustained clinical benefit from such
therapy, but preclinical mouse studies have now clearly delineated the hurdles that must be overcome to render T-cell-based antitumor
therapy effective. Contrary to earlier expectations, it is now established that remarkably potent CD4+ and CD8+ pre-effector T cells are naturally sensitized even in mice bearing progressive, weakly immunogenic
tumors. However, such T cells often display signal transduction impairments as a consequence of the
tumor environment, which limit their acquisition of optimal effector function. Extracorporealization and culture of these
tumor-sensitized T cells with appropriate activation stimuli not only restores normal signal transduction, but also confers resolute effector activity that can often sustain
tumor rejection upon reinfusion. In mouse studies, the
L-selectin(low) fraction of T cells in
tumor-draining lymph nodes (TDLN) constitutes the potent pre-effector population and comprises both CD4+ and helper-independent CD8+ T cells. Appropriate in vitro activation confers an apparently unrestricted trafficking capacity to this fraction, and even the ability to proliferate within the
tumor bed, leading to unprecedented
tumor rejection at anatomic sites (e.g., subcutaneous and intracranial) that were historically refractory to such treatment. Such results underscore the surprising capacity of appropriately activated effector T cells to withstand the immunosuppressive, tolerogenic, and apoptotic influences of the typical
tumor environment. Given the increasingly appreciated and critical communications between T cells and host Ag-presenting cells (APC), which cross-present
tumor Ag, it is likely that dendritic cell-based
vaccine maneuvers that promote sensitization of T1-committed
L-selectin(low) antitumor T cells will play an increasingly important role in adoptive
therapy strategies.