Abstract
Tumor dormancy is a phenomenon where small numbers of tumor cells persist in the host for months or years. We previously showed in the DA1-3b/C3H mouse model of acute myeloid leukemia that dormant tumor cells resist cytotoxic T-lymphocyte (CTL)-mediated killing because they overexpress B7-H1. Here, we vaccinated mice with DA1-3b cells transduced with CXCL10. Vaccinated mice developed a strong systemic immunity that led to the cure of established leukemia without persistence of dormant tumor cells. In vivo depletion of natural killer (NK) cells from the mice abrogated the protective effect of the vaccine. Long-term persistent leukemic cells resist CTL-mediated lysis but were killed by NK cells from mice vaccinated with DA1-3b/CXCL10. These NK cells expressed B7-H1. Recombinant CXCL10, CXCL9, CXCL11, and CXCL12 chemokines induced expression of B7-H1 on mouse and human NK cells in vitro. Mouse and human B7-H1+ NK cells induced proliferation of T cells and production of interferon gamma and tumor necrosis factor alpha in vitro, and in vivo blocking of B7-H1 inhibited the protective effect of vaccination. Thus, CXCL10 induces antileukemic immunity, at least partially by stimulating NK cells to express B7-H1+. This antitumor effect is in contrast to the effect of B7-H1 when expressed on tumor cells because it stops cytotoxic lymphocytes from killing those tumor cells.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
B7-1 Antigen / biosynthesis
-
B7-1 Antigen / immunology*
-
B7-H1 Antigen
-
Cancer Vaccines / administration & dosage
-
Cancer Vaccines / genetics
-
Cancer Vaccines / immunology*
-
Cell Line, Tumor
-
Cell Proliferation
-
Chemokine CXCL10
-
Chemokines, CXC / biosynthesis
-
Chemokines, CXC / genetics
-
Chemokines, CXC / immunology*
-
Female
-
Gene Expression Regulation, Leukemic / genetics
-
Gene Expression Regulation, Leukemic / immunology*
-
Humans
-
Interferon-gamma / biosynthesis
-
Interferon-gamma / immunology
-
Killer Cells, Natural / immunology*
-
Killer Cells, Natural / metabolism
-
Leukemia, Myeloid, Acute / genetics
-
Leukemia, Myeloid, Acute / immunology*
-
Leukemia, Myeloid, Acute / metabolism
-
Leukemia, Myeloid, Acute / therapy
-
Lymphocyte Depletion
-
Membrane Glycoproteins / antagonists & inhibitors
-
Membrane Glycoproteins / biosynthesis
-
Membrane Glycoproteins / immunology*
-
Mice
-
Peptides / antagonists & inhibitors
-
Peptides / immunology*
-
T-Lymphocytes, Cytotoxic / immunology
-
T-Lymphocytes, Cytotoxic / metabolism
-
Transduction, Genetic
-
Tumor Necrosis Factor-alpha / biosynthesis
-
Tumor Necrosis Factor-alpha / immunology
-
Vaccination
Substances
-
B7-1 Antigen
-
B7-H1 Antigen
-
Cancer Vaccines
-
Cd274 protein, mouse
-
Chemokine CXCL10
-
Chemokines, CXC
-
Cxcl10 protein, mouse
-
Membrane Glycoproteins
-
Peptides
-
Tumor Necrosis Factor-alpha
-
Interferon-gamma