Successful adoptive immunotherapy of
cancer requires the identification, isolation, and expansion of
tumor-specific immune effector cells. A reliable source of
tumor-immune lymphocytes is lymph nodes draining a growing
tumor. After in vitro stimulation with anti-CD3 and expansion in
IL-2, these cells are capable of mediating the regression of established
tumors. In the absence of further Ag stimulation, we recently found that the down-regulation of the homing molecule
L-selectin could serve as a
surrogate marker for isolation of specific
tumor-sensitized T cells. The
L-selectin(low) (
L-selectin-) T cells proliferated more vigorously than unfractionated or
L-selectin(high) cells. In adoptive immunotherapy of established intracranial MCA 205
tumors,
L-selectin- cells displayed at least 30-fold greater therapeutic efficacy than unfractionated cells.
L-selectin(high) cells did not demonstrate any antitumor effects. Activated
L-selectin- cells secreted a number of
cytokines, including IFN-gamma,
IL-2,
IL-4, and
IL-10, specifically when stimulated with cognate
tumor cells. Further analysis revealed that CD4 T cells alone mediated
tumor regression and secreted
cytokines. Our results thus demonstrate that the purification of
L-selectin- cells led to the generation of CD4 immune effector cells with unusually high therapeutic efficacy against chemically induced
tumors. The lack of cytotoxicity and the ability to secrete
cytokines suggest that these effector CD4 cells mediate antitumor effects through an indirect mechanism similar to the
delayed hypersensitivity reaction.