Dysregulation of telomerase activity and expression in lymphokine-activated killer cells from advanced cancer patients: Possible involvement in cancer-associated immunosuppression mechanism

There exists cancer-associated immunosuppression, and the generation of lym phokine-activated killer (LAK) cells is impaired in patients with advanced cancer. Telomerase has been reported to be upregulated in the activation of lymphocytes to proliferate against immune stimulation as well as in the ma lignant transformation of immortal cancer cells. We attempted to clarify th e involvement of telomerase in the impairment of LAK cell generation in pat ients with advanced cancer. LAK cells were generated by stimulation with in terleukin (IL)-2 and immobilized anti-CD3 antibody (IL-2/ CD3 system) from peripheral blood mononuclear cells of healthy volunteers (he-LAK) or patien ts with advanced cancer (ca-LAK), and proliferative potential of LAK cells was evaluated on the basis of population doubling level (PDL). Telomere len gth and telomerase activity of LAK cells were measured by the hybridization with oligonucleotide (TTAGGG)4 and by the telomeric repeat amplification p rotocol (TRAP) assay, respectively. Effects on telomerase activity in LAK c ells of serum from cancer patients, transforming growth factor (TGF)-beta, and IL-10 were also examined. The lifespan of ca-LAK (15.2+/-5.1 PDLs) was significantly shorter than that of he-LAK (22.6+/-8.3 PDLs) (p=0.0358). The re were no significant differences between he- and ca-LAK in telomere lengt h before IL-2/CD3 stimulation and maximal telomerase activity induced. The telomerase activity induced in ca-LAK failed to elongate sufficiently the t elomeric ends (-35.2+/-46.2 bp) compared with that in he-LAK (16.8+/-41.5 b p) (p=0.0448). The telomerase activity was initially detectable on day 2 in all he-LAK, whereas 8 (61.5%) of 13 ca-LAK expressed telomerase activity o n day 3 or later following the stimulation, showing a significant retardati on of telomerase expression (p=0.0116). The addition to the LAK cell genera tion system of serum From cancer patients, as well as IL-10, but not transf orming growth factor (TGF)-beta, suppressed the telomerase activity. This s erum-induced suppression of telomerase activity in LAK cells was abrogated with the addition of anti-IL-10 antibody but not with anti-TGF-beta antibod y. It is suggested that the dysregulation of telomerase activity and expres sion exists in LAK cells of cancer patients, resulting in the impairment of LAK cell generation in patients with advanced cancer. Serum IL-10 may be i nvolved in the impairment of LAK cell generation by the suppression of telo merase activity of lymphocytes in vivo. Thus, the dysregulation mechanism o f telomerase activity and expression in lymphocytes of cancer patients may be attributable, in part, to cancer-associated immunosuppression.