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 staphylococcal enterotoxin A (SEA) combined with a Fab fragment of a tumor-specific antibody is a highly efficient immunotherapy for mice expressing lung melanoma micrometastasis. In the present study, the systemic and local immune responses generated by this therapy were analyzed at a cellular level. Two distinct but coupled immune reactions occurred after repeated therapy. Tumor necrosis factor and macrophage inflammatory protein-1 alpha and -1 beta were immediately synthesized, in the absence of T lymphocytes, at the local tumor site in the lung. This was followed by the induction of VCAM-1 adhesion molecule expression on pulmonary vascular endothelial cells. Concurrently, the early response in the spleen was characterized by the induction of selective T cells producing interleukin (IL)-2. The primed and expanded SEA-reactive V beta 3- and V beta 11-expressing T lymphocytes accumulated to the tumor area only after Fab-SEA therapy and were not present in the lung when SEA, Fab fragment, or recombinant IL-2 was injected. The tumor-infiltrating 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 Fab-SEA-targeted antitumor immune response. These results emphasize the necessity to investigate several sites of antigen presentation to elucidate the effects of immunotherapy.
Litton
M J
MJ
Department of Immunology, Stockholm University, Sweden.
Dohlsten
M
M
Hansson
J
J
Rosendahl
A
A
Ohlsson
L
L
Kalland
T
T
Andersson
J
J
Andersson
U
U
D000818:Animals; D000912:Antibodies, Neoplasm / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004768:Enterotoxins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D000922:Immunotoxins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
D000912:Antibodies, Neoplasm; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal