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

Abstract

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.

• Authors: L A DeBruyne, A E Chang, M J Cameron, Z Yang, D Gordon, E G Nabel, G J Nabel, D K Bishop
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 43 Issue 1 Pg. 49-58 (Sep 1996) ISSN: 0340-7004 [Print] Germany
• PMID: 8917636 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CD4 Antigens
• HLA-B Antigens
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• CD4 Antigens (physiology)
• Cell Separation
• Gene Transfer Techniques
• Genetic Heterogeneity
• HLA-B Antigens (genetics)
• Humans
• Lymphocytes, Tumor-Infiltrating (chemistry, cytology, immunology)
• Melanoma (genetics, pathology)
• Receptors, Antigen, T-Cell, alpha-beta (metabolism)