TUMOR-THERAPY WITH AN ANTIBODY-TARGETED SUPERANTIGEN GENERATES A DICHOTOMY BETWEEN LOCAL AND SYSTEMIC IMMUNE-RESPONSES

Repeated injections of a fusion protein containing the superantigen st aphylococcal enterotoxin A (SEA) combined with a Fab fragment of a tum or-specific antibody is a highly efficient immunotherapy for mice expr essing lung melanoma micrometastasis. In the present study, the system ic and local immune responses generated by this therapy were analyzed at a cellular level. Two distinct but coupled immune reactions occurre d after repeated therapy. Tumor necrosis factor and macrophage inflamm atory protein-1 alpha and -1 beta were immediately synthesized, in the absence of T lymphocytes, at the local tumor site in the lung. This w as followed by the induction of VCAM-1 adhesion molecule expression on pulmonary vascular endothelial cells. concurrently, the early respons e in the spleen was characterized by the induction of selective T cell s producing interleukin (IL)-2. The primed and expanded SEA-reactive V beta 3- and V beta 11-expression T lymphocytes accumulated to the tum or area only after Fab-SEA therapy and were not present in the lung wh en SEA, Fab fragment, or recombinant IL-2 was injected. The tumor-infi ltrating T cells produced large amounts of interferon-gamma, but no IL -2 or Th2 type of lymphokines were detected at the tumor site in the F ab-SEA-targeted anti-tumor immune response. These results emphasize th e necessity to investigate several sites of antigen presentation to el ucidate the effects of immunotherapy.