Bystander elimination of antigen loss variants in established tumors.
Cancers express antigens that are targets for specific cytotoxic T lymphocytes (CTLs). However, cancer cells are genetically unstable. Consequently, sub-populations of cancer cells that no longer express the target antigen may escape destruction by CTLs and grow progressively. We show that cytotoxic T cells indirectly eliminate these antigen loss variants (ALVs) in a model system when the parental cancer cells express sufficient antigen to be effectively cross-presented by the tumor stroma. When the parental tumor expressed lower levels of antigen, cytotoxic T cells eradicated the antigen-positive parental cancer cells, but the ALVs escaped, grew and killed the host. By contrast, when the parental tumor expressed higher levels of antigen, cytotoxic T cells eradicated not only the parental cancer cells but also the ALVs. This 'bystander' elimination of ALVs required stromal cells expressing major histocompatibility complex (MHC) molecules capable of presenting the antigen, and occurred in tumors showing evidence of stromal destruction. ALVs were apparently eliminated indirectly when tumor-specific CTLs killed stromal cells that were cross-presenting antigen produced by and released from antigen-positive cancer cells. These results highlight the general importance of targeting the tumor stroma to prevent the escape of variant cancer cells.
Department of Pathology and The Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA. mspiotto@midway.uchicago.edu
Michael T
MT
Spiotto
Donald A
DA
Rowley
Hans
H
Schreiber
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000627:therapeutic use; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018183:Transplantation Chimera; D019139:Tumor Escape
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D013629:Tamoxifen; D054353:Perforin; C064658:RAG-1 protein; C016601:afimoxifene; D007371:Interferon-gamma