Immunochemotherapy against colon cancer by gene transfer of interleukin-12 in combination with oxaliplatin

Abstract

Using a murine model of liver metastases, we found that oxaliplatin can enhance the immunostimulatory effect of interleukin-12 delivered by an adenoviral vector. A shift toward a favorable immune microenvironment was observed in tumors, with a relative increase in CD8+ T cells vs. T regulatory and myeloid-derived suppressor cells.

Figure 1.

IL-12 and oxaliplatin cooperate to induce an efficient immune response against tumors. Schematic representation of experiments, including schedule and description of treatment groups (A). Hepatic tumors were established by intrahepatic inoculation of murine colon cancer cells in syngeneic C57BL/6 mice. The HC-Ad/RUmIL-12 vector was administered by direct hepatic injection in the liver surrounding the tumors, and expression of IL-12 was activated by daily injections of mifepristone (Mif). Some mice were treated with intraperitoneal chemotherapy using single agents (OXP, 5-FU, Iri or Gem, named collectively CTH). Other groups received the same drugs preceding IL-12 expression (CTH⁺IL12). The presence of tumors was evaluated by direct inspection through laparotomy one month after initiation of treatments. (B) Percentage of tumor-free animals. No tumor regressions were observed in control animals or those treated with chemotherapy alone, and are not represented in the graphic. (C) Cured animals received a subcutaneous inoculation of the same cancer cells, and the graphic shows the proportion of mice that were completely protected (absence of tumor growth). (D-E) In a separate set of experiments, tumor samples were obtained in the course of the treatments. Leucocytes were isolated and CD8⁺ T cells, Tregs (CD25⁺ FoxP3⁺) and monocytic MDSC (CD11b⁺ Ly6C+ Ly6G^-) were identified by flow cytometry. The fold increase in the ratio of CD8/Treg and CD8/MDSC for each group is represented in panels D and E, respectively, considering the control group as a reference. *p < 0.05; p < 0.005 (analysis of variance).