Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction

Abstract

To investigate antitumor mechanisms in interleukin (IL)-4 therapy, we established an IL-4-overexpressing MC38 murine colorectal cancer cell line (MC38-IL4). As a therapy against established tumors, MC38-IL4 cells were inoculated contralaterally 7 days after wild-type (MC38-WT) cells had been injected, significantly reducing growth of wild-type tumors (P ¼ 0.030). Immunohistochemical analysis showed numerous granulocytes infiltrating wild-type tumors of MC38-IL4-inoculated mice. Injection of MC38-IL4 cells in leukocytedepleted mice confirmed that granulocytes were involved in IL-4-related primary antitumor effects. Inoculation of MC38-WT in leukocyte-depleted mice initially injected with MC38-IL4 suggested that T cells contributed to the antitumor effects. To investigate tumor-specific responses, we stimulated splenocytes of MC38-immune mice with MC38-IL4 cells in vitro, resulting in MC38-specific lysis (57.577.2%, effector to target ratio ¼ 20). Treatment of established wild-type tumors with MC38-IL4 in combination with interferon (IFN)-a-overexpressing MC38 cells (MC38-IFNa) significantly reduced the growth of wild-type tumors (P ¼ 0.009). In vitro IFN-g production by splenocytes from mice injected with both MC38-IL4 and -IFNa was greatly enhanced in comparison with MC38-IL4 alone, while IL-10 production was not increased. Thus, granulocytes concern early antitumor effects of IL-4 therapy. Subsequently, IL-4 induces longlasting, tumor-specific immune responses. IL-4 appears to promote a T-helper 1-type antitumor immune response, which is enhanced in cooperation with IFN-a. Gene Therapy (2005) 12, 733-741.

Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death-1 on the growth of established tumors

“…We have previously reported that the combination of IFN-a genetransduced tumor-based vaccination therapy and IL-4 or IL-12 gene therapy suppresses the outgrowth of established tumors. 13,14 Although the suppressive effects of established tumors were observed in these cytokine combination therapy models, we did not see reductions in the size of all of the parental tumors. Therefore, further improvements in the treatment are needed before clinical application.…”

“…11 We previously reported that IFN-a-expressing tumor cells promote the survival of tumor-specific CTLs by preventing apoptosis, 12 and in addition, the combination of IFN-a gene therapy and either interleukin (IL)-4 or IL-12 gene therapy was found to suppress the outgrowth of established tumors. 13,14 Based on these immunomodulating effects of IFN-a, it has been used to treat patients with tumors, such as melanoma, renal cell carcinoma and leukemia. The programmed cell death-1 (PD-1) protein was first described as a member of the B7 family of costimulatory molecules that modulate T-cell antigen-specific receptor signaling and control Tcell activation, inactivation and survival.…”

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

“…We hypothesize that this early event was most likely mediated by eosinophils and macrophages as demonstrated by experiments using Abs that specifically blocked the accumulation of eosinophils at the site of IL-4-expressing tumors, as we (20) and others (19) have previously demonstrated. The role of the innate immunity against IL-4-expressing tumors is also suggested in our current study by the delayed growth of MCA205-IL-4 tumors in athymic mice.…”

“…This indicates that NKT cells were not responsible for the acute rejection of IL-4 expressing tumors. In contrast, in the nu/nu recipients, T cells appeared to be responsible for sustained, long-term antitumor immunity, although the delayed tumor growth in these mice suggested the potentially important role of alternate innate immune effectors, such as eosinophils, for the early phase of antitumor response (19,20).…”

Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumor-specific Th1-type immune responses

“…Our previous study and other investigations have suggested that IL-4 recruits and activates granulocytes in the microenvironment of parental tumors in order to attack and kill the tumor cells during the primary response. However, how IL-4 recruits or stimulates granulocytes in the tumor microenvironment remains unclear (4,24). Thus, IL-4 induces tumor-specific cellular immune responses, which contribute to long-lasting immunity against the parental tumors.…”