Therapeutic Efficacy of Th1 and Th2 L-selectin??? CD4+ Tumor-Reactive T Cells

Abstract

To evaluate the cytokine secretion profile and therapeutic efficacy of Th1 CD4+ L-selectin-tumor-draining lymph node lymphocytes in the treatment of murine pulmonary metastases. Prospective, murine in vivo and in vitro study. B6 mice were injected bilaterally subcutaneously with MCA 205 sarcoma cells to initiate tumor growth. Eleven days later, tumor-draining inguinal lymph nodes were harvested. Single-cell suspensions were prepared and fractionated using magnetically activated cell sorting. Sorted CD4+ L-selectin-lymphocytes were activated with anti-CD3 monoclonal antibody for 48 hours either alone to give a Th1 phenotype, or in the presence of interleukin (IL)-4 and anti-interferon-gamma (alpha-IFN-gamma) monoclonal antibody to elicit a Th2 phenotype. Activated cells were then expanded for 3 days in IL-2. Resulting cells were used to treat 3-day pulmonary metastases. Enzyme-linked immunosorbent assay and intracellular fluorescent-activated cell-sorter (FACS) scanning were used to evaluate the cytokine secretion profiles of these cells. Activated and expanded L-selectin- CD4+ T cells demonstrated a Th1 cytokine profile and excellent antitumor efficacy. In contrast, L-selectin- CD4+ lymphocytes activated in the presence of IL-4 and alpha-IFN-gamma monoclonal antibody demonstrated a Th2-like profile and significantly (P < .05) poorer antitumor efficacy. The cytokine environment during the activation of tumor-draining lymph nodes can influence the therapeutic efficacy of activated L-selectin-, CD4+ T cells. Cell mediated, Th1-dependent immunity appears to play an important role in mediating tumor regression. Culture conditions promoting Th2 cells resulted in T cells associated with diminished antitumor efficacy.