FUCTURE · Fucosylated Clusterin: a novel mechanism of tumor escape from immune response

Fucosylated Clusterin: a novel mechanism of tumor escape from immune response

Cancers represent a group of heterogeneous diseases characterized by the transformation of a normal cell into a malignant cell following a multistage process involving genome instability, mutations and tumor-promoting inflammation. Cancer is a significant public health problem worldwide and one of the major causes of mortality around the world. Among women, breast cancer is the most common type and the leading cause of death by cancer. Even if checkpoint-based therapies represent a true revolution in the treatment of metastatic cancer, a large proportion of patients do not respond to checkpoint inhibitors. Combination therapies aim at enhancing immune responses to tumors, giving checkpoint therapies a better chance to succeed. During malignant transformation that drives cancer development, tumor-associated antigens arise and they can be recognized by the immune system, generating adaptive immune responses that can lead to tumor rejection. Nevertheless, tumors generally escape immune attacks due to cancer induced immunosuppression. Unraveling the mechanisms involved in this process is a major goal to improve cancer immunotherapies. A key feature of cancer is the acquisition of glycan motifs different than those expressed by healthy tissues, a phenomenon often referred as “aberrant glycosylation”. Whereas neo expression of Sialyl Lewis X-type motifs renders neoplastic cells with the ability to bind endothelium selectins promoting metastasis, many tumors present an increased expression of non-sialylated fucosylated Lewis-type glycans, unable to bind selectins. The contribution of this glycosylation pattern to tumor growth has not been clearly characterized. Clusterin (CLU) is a multifunctional glycoprotein present in almost all tissues and body fluids. It was shown to be involved in a number of physiological and pathological processes. Indeed, its expression is dysregulated in many types of tumors, including colon, gastric, prostate, ovarian, bladder, lung and breast cancer. Our understanding of the diversity functions shared by CLU has been limited to the exitance of two isoforms: nuclear and secretory form. Different works show that CLU production is increased in different malignant tumors and even more, its overexpression is associated to an increased tumor aggressiveness and bad prognosis. However, the nature of this association is still unclear. Previous data has revealed in the glycosylation patter of seminal and serum CLU, showing that the seminal isoform bears highly fucosylated glycans, which provides it with the ability to bind to DC-SIGN, an endocytic receptor express by myeloid cells such as macrophages and dendritic cells. Moreover, binding of seminal CLU to DC-SIGN might result in the modulation of cellular function promoting a tolerogenic profile. We hypothesise that tumor secreted CLU express Lewis-type fucosylated glycans and interacts with DC-SIGN expressed by tumor infiltrating myeloid cells, favouring immunosuppressive microenvironment, thus promoting immune tolerance to tumor antigens. In this sense, fucosylated tumor CLU could represent a new mechanism of tumor escape from immune response. We propose to study the presence of fucosylated clusterin in the tumor microenvironment and unravel its immune modulatory functions.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз