Indirect CD4+ T-cell-mediated elimination of MHC II(NEG) tumor cells is spatially restricted and fails to prevent escape of antigen-negative cells.
Tumor-specific Th1 cells can activate tumor-infiltrating macrophages that eliminate MHC class II negative (MHC II(NEG)) tumor cells. Activated M1-like macrophages lack antigen (Ag) receptors, and are presumably unable to discriminate and thus kill both Ag-positive (Ag(POS)) and Ag-negative (Ag(NEG)) tumor cells (bystander killing). The lack of specificity of macrophage-mediated cytotoxicity might be of clinical importance as it could provide a means of avoiding tumor escape. Here, we have tested this idea using mixed populations of Ag(POS) and Ag(NEG) tumor cells in a TCR-transgenic model in which CD4(+) T cells recognize a secreted tumor-specific antigen. Surprisingly, while Ag(POS) tumor cells were recognized and rejected, Ag(NEG) cells grew unimpeded and formed tumors. We further demonstrated that macrophage-mediated cytotoxicity was spatially restricted to areas dominated by Ag(POS) tumor cells, sparing Ag(NEG) tumor cells in the vicinity. As a consequence, macrophage tumoricidal activity did not confer bystander killing in vivo. The present results offer novel insight into the mechanisms of indirect Th1-mediated elimination of MHC II(NEG) tumor cells.
Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
Anders A
AA
Tveita
Fredrik H
FH
Schjesvold
Olav
O
Sundnes
Ole Audun W
OA
Haabeth
Guttorm
G
Haraldsen
Bjarne
B
Bogen
D000818:Animals; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D000949:Histocompatibility Antigens Class II
Bystander killing; CD4+ T-cell immunotherapy; Macrophage cytotoxicity; Macrophage polarization; Myeloma