IL-4-Transfected Tumor Cell Vaccines Activate Tumor-Infiltrating Dendritic Cells and Promote Type-1 Immunity

Abstract

We previously demonstrated that IL-4 gene-transfected glioma cell vaccines induce effective therapeutic immunity in preclinical glioma models, and have initiated phase I trials of these vaccines in patients with malignant gliomas. To gain additional mechanistic insight into the efficacy of this approach, we have treated mice bearing the MCA205 (H-2b) or CMS-4 (H-2d) sarcomas. IL-12/23 p40−/− and IFN-γ−/− mice, which were able to reject the initial inoculation of IL-4 expressing tumors, failed to mount a sustained systemic response against parental (nontransfected) tumor cells. Paracrine production of IL-4 in vaccine sites promoted the accumulation and maturation of IL-12p70-secreting tumor-infiltrating dendritic cells (TIDCs). Adoptive transfer of TIDCs isolated from vaccinated wild-type, but not IL-12/23 p40−/−, mice were capable of promoting tumor-specific CTL responses in syngeneic recipient animals. Interestingly, both STAT4−/− and STAT6−/− mice failed to reject IL-4-transfected tumors in concert with the reduced capacity of TIDCs to produce IL-12p70 and to promote specific antitumor CTL reactivity. These results suggest that vaccines consisting of tumor cells engineered to produce the type 2 cytokine, IL-4, critically depend on type 1 immunity for their observed therapeutic efficacy.

Anti-tumor immunostimulatory effect of heat-killed tumor cells

“…For the sake of safety, a vaccine that utilizes only the tumor antigen, with no added adjuvant, and can induce a sufficient protective immune response, would be most desirable. Recent progress in the field of tumor immunology has made it feasible for live tumor cells to be transfected with cytokines, such as IL-2 or IL-12, and then perhaps used as a tumor vaccine, which could induce profound T cell immune responses Eguchi et al, 2005;Rittich et al, 2005;Shi et al, 2005;Grant et al, 2006). Although trials of such systems have proven effective in experiments, the prospect of injecting live tumor cells into an actual human body continues to be a subject of some debate.…”

Paradoxical Roles of IL-4 in Tumor Immunity

“…Interestingly, inoculation of IL-4-secreting tumors led to the rejection of non-related tumors without IL-4 producing ability in mixed tumor transplantation experiment (3). In the following years, IL-4, as a potent anti-tumor agent, was demonstrated in different tumor models, including renal cancer (4), colorectal cancer (4,5), spontaneous adenocarcinoma (6), colon carcinoma (7,8), fibrosarcoma (9,10) and melanoma (9). Okada et al compared the anti-tumor abilities of several cytokines using rat glioma (11).…”

Alternative activation of tumor-associated macrophages by IL-4

“…17,89 The importance of TAM-supplied cathepsins in tumor progression was further demonstrated by a series of bone marrow transfer experiments, in which RT2 mice were lethally irradiated prior to neoplastic development, and transplanted with bone marrow cells from cell-autonomous, and are eosinophil-dependent, although this conclusion has been challenged by other reports showing that neutrophils are instead responsible for the growth suppression of IL-4-secreting tumors. 95 In addition to eosinophils and neutrophils, dendritic cells can also be recruited to IL-4-expressing tumors, 96 and the IL-4-activated tumor-infiltrating dendritic cells were capable of promoting a tumor-specific cytotoxic T cell response 97 which was found to be important in the eradication of IL-4-expressing cells during later phases. 98,99 The finding that IL-4 expression in tumor cells leads to tumor rejection was subsequently demonstrated in different types of tumors including colon cancer, 96 renal cell cancer 100 and melanoma.…”