Rapid destruction of the tumor microenvironment by CTLs recognizing cancer-specific antigens cross-presented by stromal cells.
A single tumor contains a heterogeneous population of cancer cells. Some cancer cells express antigens and are susceptible to specific CTLs. However, other cancer cells are antigen-loss variants (ALVs) that escape these CTLs because they express little or no antigen. Here, we show that antigen-specific T cells can eliminate ALVs when the parental population expresses a model gp33 antigen (KAVYNFATM) at a level sufficient to be locally cross-presented by the nonmalignant stromal cells. That is, the ALVs are eliminated as bystanders because the stroma is destroyed. ALVs escape bystander killing when the bone marrow-derived and/or non-bone marrow-derived stroma does not express the appropriate MHC or when the amount of antigen is too low for effective cross-presentation. The rapid destruction of the stroma, including bone marrow-derived as well as sessile components, and of the parental cancer cells, may be essential for the complete rejection of established tumors by preventing variant escape.
Spiotto
Michael T
MT
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Schreiber
Hans
H
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D010446:Peptide Fragments / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D006023:Glycoproteins; D006183:H-2 Antigens; D010446:Peptide Fragments; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus