Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants.
Alteration of MHC class I molecule expression is a widespread mechanism used by tumor cells to evade T cell responses. It has long been proposed that the origin of these MHC class I-negative or -deficient tumor variants is T cell immune selection. However, there are no experimental or clinical data to substantiate this hypothesis, and this issue is currently the subject of debate. Here we report that an H-2 class I-negative fibrosarcoma tumor clone generated MHC class I-negative spontaneous lung metastases in immunocompetent syngeneic BALB/c mice. Interestingly, the same B9 clone generated MHC class I-positive metastatic nodes, under basal conditions, in athymic nu/nu BALB/c mice. This phenomenon was observed in the metastatic nodules generated after a period of in vivo growth but not in the primary tumors growing locally in the footpad. These findings support the hypothesis that the H-2 phenotype of metastatic nodes is influenced by the T cell repertoire of the host, since in the absence of this T cell pressure (i.e., in nude mice) the metastatic nodes 'recovered' H-2 class I expression. In addition, 2 different phenotypes were found when the metastatic nodules obtained from immunocompetent mice were treated with IFN-gamma. One phenotype, present in 83% of the colonies, was characterized by resistance of the Ld molecule to IFN-gamma induction, due to a deletion involving the Ld gene. The second phenotype (17% of the colonies) was similar to the original B9 clone and was characterized by the response of K, D and L class I genes to IFN-gamma. These data provide evidence that the changes in MHC class I expression during tumor development might not be random but could be predictable.
Garcia-Lora
A
A
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Spain.
Algarra
I
I
Gaforio
J J
JJ
Ruiz-Cabello
F
F
Garrido
F
F
D000818:Animals; D002469:Cell Separation; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005354:Fibrosarcoma / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018895:Microsatellite Repeats; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D018076:DNA, Complementary; D012313:RNA; D007371:Interferon-gamma