Immune factors and their role in tumor aggressiveness in glioblastoma: Atypical cadherin FAT1 as a promising target for combating immune evasion.

Abstract

Immune evasion is one of the hallmarks of cancers, including glioblastoma, the most aggressive form of primary brain tumors. Multiple mechanisms are employed by tumor cells and its microenvironment to evade immune detection and foster tumor growth and progression. The secretion of immunosuppressive molecules such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), the expression of checkpoint proteins such programmed death-ligand 1 (PD-L1), and the recruitment of T-regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) leads to suppressed immune cell activity, favoring unchecked tumor growth. The FAT atypical cadherin 1 (FAT1) has shown context/tissue-dependent effects in cancers of different tissue origins, with either oncogenic or tumor suppressor roles. Our laboratory has reported FAT1 to have an oncogenic function in glioblastoma. In addition, FAT1 promotes an immunosuppressive microenvironment in glioblastoma, reducing T-cell and monocyte infiltration while increasing immunosuppressive cells such as MDSCs. It also upregulates pro-inflammatory mediators [cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], fostering tumor-promoting signaling. This dual role in immune evasion and pro-tumorigenic inflammatory processes makes FAT1 a key driver of glioblastoma progression. This highlights the potential of FAT1 as a compelling therapeutic target. This article provides a concise overview of immune tolerance mechanisms in glioblastoma, and the crucial role of FAT1 in promoting immune tolerance and tumor advancement. In addition, this review highlights currently available immunotherapies in clinical use or undergoing trials, and the potential of FAT1 as a promising target for combinatorial therapeutic interventions.