TCR Rearrangement in Lymphocytes Infiltrating Melanoma Metastases After Administration of Autologous Dinitrophenyl-Modified Vaccine

Abstract

Administration of a vaccine consisting of autologous melanoma cells modified with a hapten, dinitrophenyl (DNP), induces T cell infiltration of metastatic sites. We have reported an analysis of these infiltrating T cells, indicating that certain TCR-Vβ gene segments are greatly overexpressed. In this study, we investigate the rearrangement of the TCR-Vβ as well as the junctional diversity in T cells infiltrating melanoma metastases following treatment with DNP vaccine. In 19 of 26 control specimens, V-D-J length analysis showed the expected polyclonal patterns. In contrast, postvaccine tumors from 9 of 10 patients showed dominant peaks of V-D-J junction size in one or more Vβ families. Dominant peaks were seen most frequently in six Vβ families (Vβ7, 12, 13, 14, 16, and 23) and were never seen in seven others. Further analysis of the oligoclonal Vβ products showed dominant peaks in the J region as well. Of particular interest was the finding that Vβ and Jβ peaks were similar in inflamed metastases obtained at different times or from different sites from the same patient. Although 6 of 10 patients expressed HLA-A1, there was no common pattern of TCR rearrangements among them. Finally, the amplified PCR products from seven of these specimens were cloned and sequenced and the amino acid sequence of the complementarity-determining region 3 was deduced. In six of seven specimens, the same complementarity-determining region 3 sequence was repeated in at least two clones and in five of seven in at least three clones. Our study indicates that DNP vaccine induces the expansion of particular T cell clones that may be agents of its antitumor effects.

Array-Based Comparative Genomic Hybridization Analysis Reveals Chromosomal Copy Number Aberrations Associated with Clinical Outcome in Canine Diffuse Large B-Cell Lymphoma

“…Moreover, one of them showed a loss in chr16, where TCR beta is located. These results are analogous to the findings observed in human melanoma after administration of a vaccine consisting of autologous melanoma cells modified with dinitrophenyl [39]. In these patients, a TCR rearrangement in lymphocytes within the lesion was found.…”

T-cell clonotypes in cancer

“…The above mentioned data were recently further substantiated by more comprehensive data on treatment induced TCR clonality in response to vaccination with hapten-modified autologous melanoma cells [74]. Thus, in 9 of 10 patients, analyses of post-vaccine biopsies showed dominant expansions in several BV families, one of which was BV14.…”

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

“…This was measured by post-therapy increment in antitumour cytolytic activity, by increased cytokine production of lymphocytes to tumour antigens and by rearranged TCR repertoire, which indicates the expansion of specific clones, in peripheral blood or within the tumour (Soiffer et al, 1998;Krause et al, 2002;Manne et al, 2002). DTH reaction to tumour cells is a useful clinical test that reflects cell-mediated antitumour immunity.…”