- Cancer vaccines employing specific cytotoxic T lymphocytes (CTL) are not efficient against tumor cells that have lost or suppressed their human leukocyte antigen (HLA) class I expression. This phenomenon is common in some cancers and particularly in metastatic lesions. Some melanomas from patients treated with ex vivo expanded T cells lose the ability to express detectable HLA class I and to present class I antigens. We show here that these defects were due to an inability to express β2-microglobulin (β2m) and were corrected by reintroduction of β2m expression. Furthermore, these β2m-deficient melanoma variants were lysed by heterologous as well as autologous natural killer (NK) lines and clones but not by T cells. The NK minority fraction but not the T majority fraction derived from heterologous lymphokine activated killer (LAK) cells kills those tumors. Intracellular adhesion molecule (ICAM)-1 expression by the different β2m deficient tumors was roughly correlated with sensitivity to lysis by NK cells. Yet, recognition of ICAM-1 and/or ICAM-2 by lymphocyte function-associated antigen (LFA)-1 expressed by NK cells in a murine model was often but not always necessary for lysis. In summary, although the requirements for NK sensitivity are not entirely clear and may vary among tumors, it is clear that T cell based immunotherapy and perhaps even normal patient T cell responses often result in the appearance of HLA class I negative metastases that are often sensitive to NK mediated lysis. Therefore, it would be useful to consider adoptive NK therapy as a supplement in the design of new cancer immunotherapies.