Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

Abstract

The CX3C chemokine fractalkine (CX3CL1) exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form chemoattracting leukocytes expressing its receptor CX3CR1. When adenoviral vector expressing mouse fractalkine (AdFKN) was transduced to the tumor cells, fractalkine was expressed as both membrane-bound form on the tumor cells and soluble form in the supernatant in vitro. Intratumoral injection of AdFKN (1Â10 9 PFU/tumor) into C26 and B16F10 tumors resulted in marked reduction of tumor growth compared to control (C26: 86.5%, p<0.001; B16F10: 85.5%, p<0.001). Histological examination of tumor tissues revealed abundant infiltration of NK cells, dendritic cells, and CD8 + T lymphocytes 3 and/or 6 days after treatment with AdFKN. Splenocytes from mice treated by AdFKN developed tumor-specific cytotoxic T cells, and thereby protected from rechallenging with parental tumor cells. Antitumor effects by AdFKN were completely abrogated in both NK celldepleted mice and CD8 -/-mice, and partially blocked in CD4 -/-mice. These data indicated that fractalkine mediates antitumor effects by both NK cell-dependent and T cell-dependent mechanisms. This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.

Effect of fractalkine-Fc delivery in experimental lung metastasis using DNA/704 nanospheres

“…Although the mechanisms by which fractalkine exerts its antitumor activity on osteosarcoma lung lesions have not been identified yet, we can suppose that innate immunity (via NK cells) and adaptive immunity (via CD8 þ T cells and/or dendritic cell) are likely to play a major role in mediating tumor regression of osteosarcoma lung metastasis as reported in colon carcinoma and in many other solid tumors development. [8][9][10][11]13,30,31 In addition to reinforcing this assumption, IL-12, which notably activates NK cells and facilitates the induction of cytotoxic and T helper type 1 T cells, [32][33][34][35] was found to inhibit the development of osteosarcoma lung metastases.…”

“…In the context of chemokinetransduced tumor cells, the overexpression of fractalkine in various experimental tumor models has been shown to promote a tumor-suppressive activity by improving the recruitment of distinct leukocytes depending on the tumor type. [8][9][10][11][12][13][14] Of interest, our group has demonstrated the T-cell-mediated immunotherapeutic potential of constitutive fractalkine expression by colon carcinoma cells. 13 More recently, mesenchymal stem cells have been used to deliver fractalkine into lung metastases of C26, Lewis lung carcinoma or B16F10 tumor mice, and resulted in a strong antitumoral effect and prolonged survival in mice.…”

“…13 More recently, mesenchymal stem cells have been used to deliver fractalkine into lung metastases of C26, Lewis lung carcinoma or B16F10 tumor mice, and resulted in a strong antitumoral effect and prolonged survival in mice. 11,15 Although cancer therapies using mesenchymal stem cells as gene carrier in humans are theoretically attractive, several issues including their tumor-promoting effects still raise potential risks in clinical applications. 16 As gene carriers have a pivotal role in cancer gene therapy, more attention must be paid to the vectors used in developing an optimal delivery system according to the therapeutic aims, the gene of interest and the tumor characteristics.…”

Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma

“…28,29 Murine colon adenocarcinoma cells C26 and melanoma B16F10 cells showed that antitumor immune response induced by FK gene transfer depended on NK and T cells. 30 However, Lavergne et al 31 reported that in the EL-4 lymphoma model, FK-mediated antitumor effects occurred only via NK cells but not T cells because this antitumor effect was observed only in T cell-and B cell-deficient Rag1-/-mice, but was ablated in NK Antitumor effect of fractalkine in liver cancer L Tang et al cell-deficient beige mice. Another study showed that no significant antitumor effect of FK was found when using an ex vivo gene transfer into OVHM tumor cells by an adenoviral vector.…”

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

“…This chemokine is critically important for infiltration (chemotaxis and adhesion) of various lineages of lymphocytes characterized by a high content of intracellular perforin and granzyme, and monocytes/macrophages expressing its receptor Endocrine-Related Cancer (2009) 16 211-224 www.endocrinology-journals.org CX3CR1 in human carcinomas (Guo et al 2003, Ohta et al 2005. Previous reports have demonstrated that the antitumor effects elicited by fractalkine gene transfer into subcutaneously implanted murine cancer cell lines depend on NK and T cells (Guo et al 2003, Lavergne et al 2003, Xin et al 2005. Consistent with our data, high endogenous fractalkine expression in neuroblastoma (Zeng et al 2007), colorectal cancer (Ohta et al 2005), and gastric adenocarcinoma (Hyakudomi et al 2008), where it is mainly observed in the plasma membrane and cytoplasm of tumor cells, correlated with a higher density of tumor-infiltrating immune cells.…”