The combined actins of NK and T lymphocytes are necessary to reject a transplantable mesenchymal tumor through mechanisms partly dependent on KG2D

Proc Amer Assoc Cancer Res, Volume 47, 2006 620 Better understanding of the mechanisms that mediate spontaneous immune rejections of mouse tumors ought to be important in the quest for improvements in immunotherapy of cancer. A set of intraperitoneal tumors of mesenchymal origin that had been chemically induced in ubiquitously expressing EGFP transgenic mice provided a model in which both T and NK cells were absolutely required for tumor rejection. Tumor cells were green fluorescent and readily grafted in RAG1-/- immunodeficient mice, while they were majoritarily rejected in syngeneic C57BL/6 and EGFP-transgenic mice. Tumor cell clones with the highest EGFP expression tended to be rejected in immunocompetent mice, but a direct involvement of EGFP as the antigen recognized for the immune rejections was ruled out. Rejections were absolutely dependent on NK cells as well as on CD4+ and CD8+ T lymphocytes. The effects of IFN-γ were required only at the malignant cell level. The progressing variants of the tumor in syngeneic mice were rejected in (C57BL/6 x BALB/c) CB6F1 mice in a NK dependent fashion, indicating that semiallogeneic NK cells were superior at the rejection of these tumors. NK recognition of tumor cells was at least in part mediated by the NKG2D activating receptor, but blocking its function in vivo only partially interfered with the rejection in syngeneic mice, indicating the in vivo activity of additional NK receptors. Rejection needs a concerted set of activities that are mediated by NK and T cells, that on the NK part include early destruction of tumor cells, and provision of cell debris for T-cell crosspriming by DC, as well as production of proinflammatory cytokines. NK cells were also readily detected in the tumor-rejecting leukocyte infiltrates.