DIFFERENT CYTOKINE PROFILES RELEASED BY CD4(-DRAINING LYMPH-NODE CELLS INVOLVED IN MEDIATING TUMOR-REGRESSION() AND CD8(+) TUMOR)

We have previously demonstrated that the growth of weakly immunogenic murine sarcomas leads to the induction of immunologically specific pre -effector cells in tumor-draining lymph nodes (TDLN). The in vitro act ivation of TDLN cells with anti-CDS monoclonal antibodies (mAbs) and i nterleukin-2 (IL-2) resulted in the acquisition of effector function a s measured by tumor regression in the adoptive immunotherapy of pulmon ary metastases. Further studies were performed to characterize the mec hanisms associated with in vivo tumor reactivity mediated by activated TDLN cells. By positive selection, CD4(+) and CD8(+) T cells were pur ified and activated by the anti-CD3/IL-2 method. CD8(+), but not CD4(), cells manifested tumor-specific granulocyte-macrophage colony-stimu lating factor (GM-CSF) and interferon-gamma (IFN-gamma) release in vit ro, and elicited tumor regression in vivo. By contrast, only activated CD4(+) were found to release significant amounts of IL-2 in response to tumor antigen but did not mediate tumor regression in vivo. Mixing the two purified populations enhanced the antitumor activity of the CD 8(+) T cells. In culture, IL-2 was found to augment the relative amoun t of tumor-specific release of GM-CSF and IFN-gamma by activated TDLN cells. We found that the tumor-specific release of GM-CSF and IFN-gamm a by activated lymphocytes was strongly associated with the in vivo th erapeutic efficacy of these cells. Evidence in support of this include d the following: (1) cytokine release of TDLN derived after different durations of tumor growth correlated with tumor reactivity in adoptive transfer studies, (2) cytokine release of T cells derived from differ ent lymphoid organs corresponded with tumor reactivity in adoptive tra nsfer, and (3) in vivo administration of neutralizing mAb to IFN-gamma and GM-CSF significantly inhibited the antitumor reactivity of TDLN c ells. These studies document the contributory roles of IFN-gamma, GM-C SF, and IL-2 released by activated CD4(+) and CD8(+) T cells involved in tumor regression.