In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis.
In tumor dormancy, tumor cells persist in the host over a long period of time but do not grow. We investigated in the DA1-3b mouse model of acute myeloid leukemia how leukemic cells could persist for months in spite of an effective antileukemic immune response. Mice were immunized with irradiated interleukin 12 (IL12)- or CD154-transduced DA1-3b cells, challenged with wild-type DA1-3b cells, and randomly killed during 1-year follow-up. Quantification of residual disease 1 year after challenge showed that persistent leukemic cells represented less than 0.02% of spleen cells in most animals. These residual cells were still able to kill naive hosts, even when isolated after 1 year of persistence. Persistent leukemic cells were more resistant to specific cytotoxic T-cell (CTL)-mediated killing and had enhanced B7-H1 and B7.1 expression proportional to the time they had persisted in the host. Blocking B7-H1 or B7.1/cytotoxic T-lymphocyte-associated antigen (CTLA-4) interaction enhanced CTL-mediated killing of the persistent cells, and blocking B7-H1, B7.1, or CTLA-4 in vivo prolonged survival of naive mice injected with persistent leukemic cells. Thus, escape of leukemic cells from tumor immunity via overexpression of B7-H1 or B7.1 might represent a new mechanism of tumor dormancy in acute leukemia.
Saudemont
Aurore
A
Unité INSERM 524, Institut de Recherche sur le Cancer de Lille, Lille, France.
Quesnel
Bruno
B
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry; D018122:B7-1 Antigen / Q000737:chemistry / Q000276:immunology*; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000737:chemistry / Q000276:immunology*; D023201:CD40 Ligand / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000096:biosynthesis; D007938:Leukemia / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D008809:Mice, Inbred C3H; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D010455:Peptides; D023201:CD40 Ligand; D018664:Interleukin-12