MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components.
Previous reports from our group indicated that the MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosarcoma tumor clone (B9) were, depending on the immune status of the host, MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. Now we report the identification of the molecular alterations responsible for the changes of MHC class I molecules in both situations. Metastatic nodes were analyzed for the mRNA level of H-2 class I and beta2-microglobulin genes, and several gene components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM). These included the genes coding for the low-molecular-weight proteins LMP2, LMP7, LMP10, the transporter associated with antigen processing (TAP-1, TAP-2), and calnexin, calreticulin, tapasin, PA-28-alpha, PA-28-beta, ERP-59 and ER-60. Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice. In contrast, similar techniques with mRNA preparations obtained from metastatic nodes from immunodeficient mice showed that the mRNA expression level of these genes was highly positive. Interestingly, the MHC class I-positive or negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity. H-2 positive metastasis grew more slowly than the H-2 negative ones when injected intrafootpat in syngeneic immunocompetent animals and were finally rejected. These results provide evidence of the role of T cells in immune surveillance against tumors and identify a mechanism targeted by antitumor T lymphocytes to generate MHC class I-negative tumor escape variants.
Garcia-Lora
Angel
A
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.
Martinez
Marisol
M
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.
Algarra
Ignacio
I
Departamento de Ciencias de La Salud, Universidad de Jaén, Jaén, Spain.
Gaforio
Jose Juan
JJ
Departamento de Ciencias de La Salud, Universidad de Jaén, Jaén, Spain.
Garrido
Federico
F
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000556:secondary; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018895:Microsatellite Repeats; D009097:Multienzyme Complexes; D010641:Phenotype; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019139:Tumor Escape; D001613:beta 2-Microglobulin / Q000235:genetics
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006183:H-2 Antigens; D009097:Multienzyme Complexes; D012333:RNA, Messenger; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D001613:beta 2-Microglobulin; C071313:LMP-2 protein; C071692:TAP2 protein, human; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex