Abstract
Simple SummaryCancer immunotherapy is gaining attention as a potential fourth treatment following surgery, chemotherapy, and radiation therapy. Cancer stem cells have recently been recognized and validated as a key target for cancer treatment. Cripto-1, which is a GPI-anchored membrane-bound protein that functions as a co-receptor of Nodal, is a marker of cancer stem cells. Since Nodal is a member of the TGF-β family, which performs an important role in stem cells and cancer stem cells, the inhibition of Cripto-1 could be a strategy by which to block Nodal signaling and thereby suppress cancer stem cells. We propose that Cripto-1 may be a novel target for cancer immunotherapy.The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, and CTLA4, is an effective treatment method. However, no immunotherapeutic target has been found that retains validity in the face of tumor diversity. The transforming growth factor (TGF)-β cytokine family possesses broad biological activity and is involved in the induction and/or transdifferentiation of helper T cells, which are important in immunotherapy. Nodal is a member of the TGF-β family playing important roles in tissue stem cells and cancer stem cells (CSCs), interacting with the co-receptor Cripto-1, as well as with Activin type IB (Alk4) and Activin typeIIreceptors, and maintaining stemness and Notch and Wnt/β-catenin signaling in CSCs. In recent years, it has been reported that Cripto-1 could be a potential therapeutic target in CSCs. Here, we review the accumulated literature on the molecular mechanisms by which Cripto-1 functions in CSCs and discuss the potential of Cripto-1 as an immunotherapeutic target in CSCs.
Highlights
Since van der Bruggen et al first identified a human melanoma antigen recognized by cytolytic T cells in 1991 [1], tumor immunogenicity has been studied by many researchers as a potential feature to target in cancer treatment [2]
To enhance T cell activation, Immune checkpoint inhibitors (ICIs) inhibit the interaction of T cells and cancer cells mediated by PD1 and programmed death-ligand 1 (PD-L1), which enables cancer cells to escape from T-cell attack; ICIs’ mechanism of action is different from that of conventional cancer immunotherapy that directly boosts immunity as a method by which to attack cancer cells
Helper T cells, which are important in immunotherapy, are transdifferentiated by transforming growth factor (TGF)-β, while transforming growth factor β (TGF-β) inhibits the differentiation of cytotoxic T lymphocytes (CTLs)
Summary
Since van der Bruggen et al first identified a human melanoma antigen recognized by cytolytic T cells in 1991 [1], tumor immunogenicity has been studied by many researchers as a potential feature to target in cancer treatment [2]. Tauriello et al reported that inhibition of TGF-β causes a strong and persistent cytotoxic T cell response against tumor cells, which prevents metastasis They showed that increased TGF-β in the tumor microenvironment is a major mechanism of immune avoidance by promoting T cell elimination and blocking the acquisition of the T helper 1 (Th1) effector phenotype in advanced colorectal cancer [14]. Mariathasan et al reported that enhanced TGF-β signaling in patients’ fibroblasts reduced patients’ responses to treatment in a cohort study analyzing specimens from patients with metastatic urothelial cancer These authors showed that the therapeutic co-administration of anti-TGF-β antibody and anti-PD-L1 antibody reduced TGF-β signaling in stromal cells and promoted T cell penetration into the center of the tumor [15]. The molecular function of Cripto-1 in CSCs is discussed together with the potential of Cripto-1 as a target for CSC immunotherapy
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