Anti-tumor effect of combining CC chemokine 22 and an anti-CD25 antibody on myeloma cells implanted subcutaneously into mice

Abstract

Abstract. Chemokines are known to have anti-tumor effects due to their chemoattractant properties, which stimulate the accumulation of infiltrating immune cells in tumors. CCL22 (macrophage-derived chemokine, MDC) attracts killer T cells, helper T cells and antigen-presenting cells expressing the CCL22 receptor, CCR4. Thus, CCL22 gene expression results in the accumulation of these cells in tumors, and has been shown to suppress lung and colon cancer growth in mice. In the present study, early-stage subcutaneous tumor growth in a mouse multiple myeloma cell line stably expressing CCL22 (MPC-CCL22) was decreased compared to tumor growth in control cells (MPC-mock). However, the final extent of tumor growth in these cell lines was almost equivalent. Regulatory T cells, which express CD25, CD4 and CCR4, are known to cause immune disruption. We therefore investigated the association of regulatory T cells with the progressive decrease in CCL22 anti-tumor effect observed in late-stage experimental multiple myelomas. Tumor growth in MPC-CCL22 cells was observed to drastically decrease, to the point of complete tumor regression, when CD4 or CD25 T cells were depleted. Here, we document the drastic anti-tumor effect of a combination of CCL22 and anti-CD25 antibody on multiple myeloma cells. IntroductionChemokines are a family of small cytokines that primarily induce the directed migration of hematopoietic cells when bound to their seven-transmembrane, G protein-coupled receptors (1,2). Because they function as chemoattractants for several immune effector cell types, chemokines are attractive candidates for immune cell-based approaches to cancer gene therapy. Several studies describe the anti-tumor effects induced by infiltrating immune cells upon their chemokine-mediated accumulation within the tumor mass. The regression of XCL1 (lymphotactin)-expressing engineered myeloma was mediated by increased infiltration of T cells, neutrophils and macrophages, leading to a reduction in tumorigenicity (3,4). CCL22 (macrophage-derived chemokine, MDC) is a CC chemokine that appears to be specifically secreted by a macrophage. CCL22 is a potent chemoattractant for CD8 and CD4 T cells, as well as for dendritic cells expressing the CCL22 receptor CCR4 (5,6), and is involved in chronic inflammation mediated by the continuous homing of dendritic cells and lymphocytes (7,8). Solid tumor growth in mice was suppressed by the recruitment of these cell types into tumors induced to express CCL22 using an adenoviral vector (9). Due to its tendency to function as a chemoattractant for killer T cells, helper T cells and antigen-presenting cells, CCL22 is considered to be an attractive candidate gene for immune cell-based cancer therapy. However, one drawback for such CCL22-based therapy is the immunosuppressive condition caused by the fact that CCL22 also recruits regulatory T cells into the tumor mass. Here, we demonstrate that a drastic anti-tumor CCL22 effect can be sustained in multiple myeloma tumors by reducing the recruitment of regulatory...

Identification of predictive circulating biomarkers of bevacizumab-containing regimen efficacy in pre-treated metastatic colorectal cancer patients

“…Accordingly, high baseline levels of MDC in our responding patients support its role in promoting an immune response by T-helper cells recruitment . In vivo MDC has been shown to suppress lung and colon cancer growth (Cho et al , 2009). Moreover, an MDC-increased gene expression in tumour tissue turned out to be a favourable prognostic factor (Nakajima et al , 2006) and its concentration levels strongly correlates with the frequency of FOXP3-positive cells (Mizukami et al , 2008).…”

The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

“…The specific recruitment of Tregs results in immune suppression in the advanced stages of ovarian cancer [67]. The paradox that early stage tumors are inhibited by infiltrating antitumor immune cells which is reversed by suppressive Tregs through CCR4/CCL22 interaction is also observed in myeloma [68]. Thus, chemokines and GPCRs play a crucial role in regulating pro- and antitumor responses by recruiting different types of immune cells (Table 2).…”