Direct transfer of a foreign MHC gene into human melanoma alters T cell receptor Vβ usage by tumor-infiltrating lymphocytes

• Published in: Cancer Immunology, Immunotherapy Vol. 43; no. 1; pp. 49 - 58
• Main Authors: DEBRUYNE, L. A, CHANG, A. E, CAMERON, M. J, YANG, Z.-Y, GORDON, D, NABEL, E. G, NABEL, G. J, BISHOP, D. K
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-09-1996
• Subjects: Antineoplastic agents; Biological and medical sciences; CD4 Antigens - physiology; Cell Separation; Gene Transfer Techniques; Genetic Heterogeneity; HLA-B Antigens - genetics; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating - chemistry; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Melanoma - genetics; Melanoma - pathology; Pharmacology. Drug treatments; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Antineoplastic agent; HLA-System; Variable region; Major histocompatibility system; Beta-Peptide chain; Cellular immunity; Allogeneic system; Direct method; Gene; Immunotherapy; Mechanism of action; Vector; Class I histocompatibility antigen; Human; T cell receptor; Immune response; Melanoma; Liposome; Intratumoral administration; Tumor infiltrating lymphocyte; Malignant tumor; Genetic transfer; Treatment; Gene therapy; HLA-B-Locus
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s002620050303

The direct introduction of foreign genes into tumors shows promise as a therapeutic modality to enhance tumor immunogenicity. Hence, melanoma nodules were directly injected with a vector encoding an allogeneic MHC class I molecule, HLA-B7. Tumor-infiltrating lymphocytes (TIL) were isolated from cutaneous melanoma biopsies before and after HLA-B7 gene transfer. TIL were expanded in interleukin-2 (IL-2) by standard techniques for approximately 4 weeks, then analyzed for T cell receptor V beta usage by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Prior to gene transfer. TIL V beta usage was found to be highly restricted, the only one to four V beta families being expressed and one or two of these families representing more than 90% of the repertoire. As anticipated, TIL V beta usage varied among patients expressing different HLA types. However, V beta 13 was over-represented in that six of eight patients utilized V beta 13 as a dominant family, regardless of HLA type. Following HLA-B7 gene transfer, TIL V beta usage was markedly altered: (1) V beta families that dominated following gene transfer differed from the V beta families utilized by TIL prior to treatment, and (2) introduction of the HLA-B7 gene resulted in a more diverse repertoire with an increase in the number of V beta families represented. In two patients, TIL were evaluated before treatment and from multiple, distinct melanoma nodules following gene transfer. In these two patients, a comparison was made between TIL V beta profiles obtained after treatment from nodules that had been injected with the HLA-B7 gene or left untreated. Interestingly, the V beta repertoires of TIL from uninjected nodules following gene transfer were similar to that of TIL from injected nodules, rather than pretreatment TIL. These data demonstrate a direct immunological effect of foreign MHC gene transfer into human melanoma, and suggest that local expression of an allogeneic MHC molecule generates systemic alterations in the antitumor immune response.