Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors

Abstract

Human telomerase reverse transcriptase (hTERT) is the catalytic component of a functional telomerase complex, which is important in maintaining cell immortality. In most normal human adult cells, the expression of telomerase is very low and/or transient. In contrast, almost 90% of human tumors express a relatively high level of telomerase implying the possibility of using hTERT as a universal candidate tumor antigen. In this study, we show that human monocyte-derived dendritic cells (DCs) lack telomerase activity. Similar to other normal somatic cells, DCs express the RNA (hTR) component but not the catalytic component, hTERT. We also show that telomerase activity could be reconstituted using either lipid-mediated transfection of the hTERT plasmid DNA or transduction with an E1-, E3-deleted adenoviral vector containing the hTERT gene. However, relative to plasmid transfection, adenoviral gene transfer produced higher levels of hTERT expression. Nine of 10 AdhTERT-transduced DCs were able to generate CTL responses, while only three of nine plasmid-transfected DCs did. CTLs primed against hTERT exhibited killing of telomerase positive but not telomerase negative tumor lines of diverse tissue origins. Antigenic specificity of these T cells to telomerase was further determined by introducing hTERT gene into a telomerase negative cell line, U2OS, by adenoviral transduction. Although some antigenic specificity was directed against adenoviral epitopes, the majority of CTLs were targeted against telomerase-derived antigen(s). Thus, the hTERT gene, particularly as delivered via the recombinant adenovirus, may be useful as vaccine to induce specific T-cell-mediated tumor immunity in cancer patients. In addition, our results suggest that telomerase activity and/or telomerase expression after hTERT gene transfer have a predictive value in the success of hTERT/DC-based cancer vaccination.

Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

“…Transcriptional upregulation of the hTERT catalytic unit gene expression has been observed with greater than 90% of human cancers. 25,39 This ubiquitous expression in tumors has made telomerase a very attractive target for several types of therapeutic modalities for cancer including immunotherapy, [40][41][42][43] gene therapy [32][33][34][35] and, as described in this report, oncolytic virotherapy. We and others have demonstrated the safety and efficacy of intratumoral delivery of replication-deficient, recombinant adenoviruses in which the hTERT promoter was used to drive either proapoptotic genes [32][33][34] or HSV-TK gene in combination with GCV.…”

Transgene expression of α tumor necrosis factor with mutations D142N and A144R under control of human telomerase reverse transcriptase promoter eradicates well-established tumors and induces long-term antitumor immunity

“…53 The widespread expression of telomerase in tumors indicated that peptide fragments of hTERT could serve as tumor-specific antigens and this has been confirmed by some recent reports. 54,55 Therefore, another part of the antitumor immunity may be derived from the anti-hTERT CTL responses. Taken together, we showed that the mutant TNF-a with mutations at D142N and A144R has less in vitro cytotoxic effect, but maintains its functional effect in the stimulation of T-cell proliferation.…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…This produced immortalized DCs that were shown to induce a cytotoxic T cell response both in vitro and in vivo. 128,129 Inhibition of apoptosis The major pathway targeted by these cytokines affecting apoptosis is through the anti-apoptotic Bcl-2 protein. Studies have shown IL-2, IL-7, and IL-15 all to decrease apoptosis and enhance survival of both NK and CD8 C T cells by upregulation of Bcl-2.…”