Predominant Expression of CCL2 at the Tumor Site of Prostate Cancer Patients Directs a Selective Loss of Immunological Tolerance to CCL2 That Could Be Amplified in a Beneficial Manner

Abstract

We have previously shown that, during inflammatory autoimmune diseases in humans, the immune system develops a neutralizing auto-Ab–based response to a very limited number of inflammatory mediators, and that amplification of each response could be beneficial for the host. Our working hypothesis has been that this selective breakdown of immunological tolerance is due to a predominant expression of an inflammatory mediator at an immune-restricted site undergoing a destructive process. All three conditions also take place in cancer diseases. In this study, we delineate this hypothesis for the first time in a human cancer disease and then explore its clinical implications. We show that in primary tumor sections of prostate cancer subjects, CCL2 is predominantly expressed at the tumor site over other chemokines that have been associated with tumor development, including: CXCL12, CXCL10, CXCL8, CCL3, and CCL5. Subsequently, the immune response selectivity mounts an Ab-based response to CCL2. These Abs are neutralizing Abs. These findings hold diagnostic and therapeutic implications. The current diagnosis of prostate cancer is based on prostate-specific Ag measurements that do not distinguish benign hypertrophy from malignancy. We show in this study that development of anti-CCL2 Abs is selective to the malignant stage. From a clinically oriented perspective, we show, in an experimental model of the disease, that DNA-based amplification of this response suppresses disease, which has implications for a novel way of therapy in humans.

Dissecting the Autocrine and Paracrine Roles of the CCR2-CCL2 Axis in Tumor Survival and Angiogenesis

“…We have recently shown that CCL2 is predominantly expressed at the human primary tumor site of patients suffering from CaP, which leads to selective breakdown of immunological tolerance resulting in a production of anti-CCL2 autoantibodies that are likely to participate in the regulation of disease [16].…”

A MCP1 fusokine with CCR2-specific tumoricidal activity

“…Intriguingly, non-hematological epithelial malignancies, such as prostate cancer, have been found to be addicted to CCL2 for their survival and malignant behaviour [25,26]. Furthermore, an astonishingly high proportion of primary human glial tumors overexpress CCR2 (whilst normal brain structures do not), suggesting possibly a similar mechanistic bonding to CCL2 [24].…”

The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

“…Moreover, melanoma-infiltrating M-MDSCs displayed CCR2-dependent immunosuppressive activities in the presence of GM-CSF [74]. In the transplantable prostate cancer mouse model, it has been recently demonstrated that CCL2-CCR2 interaction plays a pivotal role in the recruitment of bone marrow-derived myeloid cells to the blood and their subsequent migration into the tumor site [76,77]. …”

“…Prostate and breast carcinomas, melanomas, colorectal cancer and Lewis lung carcinoma were found to produce various chemokines (including CCL2, CCL3, CCL4, CCL5, etc. ), which were described to attract MDSCs and to maintain their suppressive activity [76,77,78,79,80]. Direct CCL2 targeting [122] or the inhibition of its production [123] has been reported to decrease the frequency of tumor-infiltrating MDSCs, to restrict neoangiogenesis and to suppress the growth of transplantable tumors.…”