Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity

Abstract

Summary In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-y monoclonal antibody (MAb) co-administration. These results strongly suggest that the antitumour effect of IL-12 is principally mediated by IFN-y release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis.

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

“…17 In particular, anti -H5V hemangiosarcoma responses were found to be potentiated by IFN and IL -12, while they were abrogated by anti -T-cell antibodies. 17,19,39 Our analysis of H5V lesions expression profiles indicated that inhibition of disease development in infected mice was associated with the persistent infiltration of stagnating tumors with activated effectors (CTL and NK ) cells. Thus, we hypothesize that the parvovirus -mediated toxicity of NS1 for H5V cells stimulated intrinsic immune reaction, and that this response was intensified when the virus expressed IP -10 transgene in addition to its own NS1 and NS2 genes.…”

“…The antitumor protection provided by MVMp / IP -10 is quite impressive because H5V model is an especially aggressive case of experimental hemangiosarcomas, which are usually refractory to complete cure by various treatments, 16,39,44,45 with IL-12 therapy being the most successful one. 19 The antineoplastic activity of IP -10 is not without precedents, although the use of different delivery systems and tumor models precludes published data from being quantitatively compared with the present ones. The most powerful protection was observed using plasmocytoma cells stably transfected with an IP-10-expressing plasmid.…”

“…15 -17 One of the most potent anticancer cytokines, IL -12, has been shown to suppress progression of experimental hemangiomas. 18,19 IP -10 (interferon -inducible protein with molecular weight of 10 kDa, recently classified as CXCL10 ) has been identified as a major IL -12-induced downstream effector of antitumor reactions, and found to inhibit the growth of several experimental tumors with varying efficacy, depending on the model and method of delivery. 20 -26 Although the mechanism of IP -10 -induced tumor suppression has not yet been fully elucidated, both antiangiogenic and immune system -mediated effects appear to be essential to the antitumor activity of this chemokine in vivo.…”

New insights into IL-12-mediated tumor suppression

“…delivery of recombinant IL-12 leads to reduced or delayed tumor growth and increased survival in transplantable, carcinogen-induced and spontaneous tumors arising in genetically modified mice. [55][56][57] It is by now clear that the antitumor effectiveness of IL-12 is dose and context dependent. 40,55,58 Delivery of IL-12 for therapeutic purposes has thus far been accomplished through direct infusion of the recombinant protein, by gene therapy using viral and non-viral vectors, electroporation, by IL-12-containing microspheres and nanoparticles or by the transfer of IL-12-overexpressing stromal and immune cell types ( Figure 2).…”

Angiosarcoma of the scalp treated with OK‐432 and rIL‐2

“…This may explain why the single therapy with rIL‐2 did not show any remarkable effects. On the other hand, IL‐12 reportedly has effects on AS, and it also induces LAK cell activity, but these effects are not interrupted by IL‐4 14–16 . According to these facts, we assume that OK‐432 may induce LAK activation directly and via IL‐12.…”