NKG2D-Mediated antitumor activity by tumor-infiltrating lymphocytes and antigen-specific T-cell clones isolated from melanoma patients

Purpose:The role of NKG2D receptor in antitumor immunosurveillance has not been completely clarified. We addressed this issue by investigating the involvement of this receptor in tumor-specific immunologic response in melanoma patients. Experimental Design: We determined the presence of NKG2D(+) Tcells among tumor-infiltrating lymphocytes (TIL) of 10 (one primary and 9 metastatic) melanoma samples and the expression of NKG2D ligands (NKG2DL) by these tumor cells. Moreover, the expression of NKG2D was assessed in a panel of antigen-specific T lymphocytes isolated from melanoma patients and the engagement of NKG2D in antitumor activity mediated by these T cells was determined. Results: TILs located either in the periphery or within the tumor mass of melanoma samples expressed NKG2D and the expression of this receptor by T cells was retained after in vitro culture. However, NKG2DLs were weakly expressed, or not expressed, by most metastatic lesions with only the primary tumor being positive for all these molecules. In contrast, these ligands were expressed, although heterogeneously, by all in vitro established melanoma lines. Moreover, the engagement of NKG2D occurred in antitumor activity by both freshly isolated and in vitro cultured TILs. However, this receptor was involved to a different extent in the antitumor activity of antigen-specific T-cell clones. Conclusions: These findings indicate that NKG2D(+) Tcells have a role in the immunologic response against tumor. Thus, new immunotherapeutic treatments for melanoma patients should be designed aimed at augmenting the NKG2D(+) T lymphocyte-mediated immune response.