title: Oncogene-targeting T cells reject large tumors while oncogene inactivation selects escape variants in mouse models of cancer.
abstract: The genetic instability of cancer cells frequently causes drug resistance. We established mouse cancer models, which allowed targeting of an oncogene by drug-mediated inactivation or monospecific CD8(+) effector T (T(E)) cells. Drug treatment of genetically unstable large tumors was effective but selected resistant clones in the long term. In contrast, T(E) cells completely rejected large tumors (≥500 mm(3)), if the target antigen was cancer-driving and expressed in sufficient amounts. Although drug-mediated oncogene inactivation selectively killed the cancer cells and left the tumor vasculature intact, which likely facilitated survival and growth of resistant clones, T(E) cell treatment led to blood vessel destruction and probably "bystander" elimination of escape variants, which did not require antigen cross-presentation by stromal cells.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Anders
authors.forename: Christian
authors.initials: C
authors.lastname: Buschow
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Ana
authors.initials: A
authors.lastname: Milojkovic
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Thomas
authors.initials: T
authors.lastname: Kammertoens
authors.forename: Peter
authors.initials: P
authors.lastname: Daniel
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Jehad
authors.initials: J
authors.lastname: Charo
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D017930:Genes, Reporter; D042822:Genomic Instability; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009857:Oncogenes; D017354:Point Mutation; D016038:Skin Transplantation; D013274:Stomach Neoplasms / Q000628:therapy; D015534:Trans-Activators / Q000235:genetics; D019139:Tumor Escape / Q000235:genetics*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; D015534:Trans-Activators; D007371:Interferon-gamma; D049409:Luciferases, Firefly