Potent effector function of tumor-sensitized L-selectin(low) T cells against subcutaneous tumors requires LFA-1 costimulation

OBJECTIVE: Animal tumor models have demonstrated that adoptive transfer of tumor-draining lymph node (TDLN)T lymphocytes can cure established tumors i n many anatomic sites. However, subcutaneous tumors are relatively refracto ry and have required maximally tolerated doses of cells. The goals of this study were to determine whether a subset of TDLN T lymphocytes varying in e xpression of the cell adhesion molecule L-selectin (CD62L) had augmented th erapeutic efficacy and to determine the cc-stimulatory requirements for tra fficking and anti-tumor effector function. STUDY DESIGN: TDLNs were recovered from mice bearing progressive MCA 205 fi brosarcomas, and the T lymphocytes were segregated into CD62L(low) and CD62 L(high) subsets and activated ex vivo with anti-CD3 mAb and IL-2, Mice bear ing established subcutaneous MCA 205 tumors were treated with activated T c ell subsets and in some experiments with additional mAb against cell adhesi on molecules. RESULTS: Adoptive transfer of as few as 5 x 10(6) activated cells cured mic e bearing 3-day subcutaneous MCA 205 tumors initiated with 6 x 106 cells, a nd the tumors demonstrated a dense infiltrate of CD62L(low) cells. In marke d contrast, adoptive transfer of 10 times as many T cells derived from the reciprocal CD62Lhigh compartment had no effect on tumor growth. The effecto r function of the CD62L(low) T cells was clearly dependent on co-stimulatio n through the cell adhesion molecule LFA-1,because anti-LFA-1 mAb completel y abrogated the antitumor reactivity of the transferred cells against subcu taneous tumors and inhibited tumor infiltration, In contrast, blockade of I CAM-1,VLA-4, or VCAM-1 had no inhibitory effect on the anti-tumor function. CONCLUSION: These studies demonstrate the high therapeutic activity of the CD62L(low) subset of tumor-draining LN T cells against subcutaneous tumors, a relatively refractory site, and confirm the essential role of LFA-1 for effector T cell function. SIGNIFICANCE: Identification of the phenotype and requirements for effector function of T lymphocytes sensitized to tumor antigens has implications fo r clinical trials of adoptive immunotherapy for head and neck carcinoma usi ng a similar approach.