Thus, anti-Treg levels must delicately balance regulatory immune cells to maintain immune homeostasis. 26 27 Anti-Tregs are a natural part of the immune system they kill immunosuppressive cells to curtail local immune suppression. 20–25 The function of these pro-inflammatory, auto-reactive T cells is opposite to regulatory cells and they are therefore termed anti-regulatory T cells (anti-Tregs). Previously, we have demonstrated that naturally occurring T cells specifically targeted immunosuppressive proteins, such as indoleamine 2,3-dioxygenase (IDO), programmed death ligand 1 (PD-L1)/L2, and arginase-I/II. 17 Thus, several cells in the PC TME increase local immune suppression by expressing TGF-β. 19 CAFs display several tumor-promoting properties, including the secretion of immunosuppressive cytokines, including TGF-β. 17 18 CAFs are attracted to and activated by inflammatory cytokines, such as TGF-β, in the TME. These cells secrete collagen into the TME, which results in the fibrotic/desmoplastic stroma characteristic of PC. 10 16 Another important regulatory immune cell in PC is the cancer-associated fibroblast (CAF). 15 Tumor-derived TGF-β converts naïve T cells (Tn) to Tregs, and the level of tumor infiltrating Tregs in PC is inversely correlated with OS.
12–14 All these cell types express TGF-β 7 and high TGF-β levels in PC tissue are associated with reduced overall survival (OS). 8 9 In addition, regulatory immune cells, such as regulatory T cells (Tregs), 10 11 tumor associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs) and neutrophils infiltrate the tumor microenvironment (TME) in PC. 6 7 In PC, transformed cells secrete TGF-β. It displays both profibrotic and immunosuppressive properties. TGF-β is a pleiotropic cytokine important in organogenesis and embryogenesis. One potential target is the cytokine, transforming growth factor-β (TGF-β). The low clinical response to ICI in patients with PC suggests that other immunosuppressive mechanisms in PC should be targeted to improve the clinical response.
5 A clinical benefit rate of 37.2% was observed in the combination group, however only 14% of patients achieved a partial response. 2–4 Recently, a phase II trial in patients with refractory metastatic PC (CheckPAC) investigated nivolumab with or without ipilimumab combined with stereotactic body radiotherapy (SBRT). Several trials that investigated the ICI in patients with advanced PC failed to demonstrate clinically relevant efficacy. In particular pancreatic cancer (PC) remains highly refractory to ICI. 1 However, not all cancers are sensitive to ICI. The discovery of the immune checkpoints, cytotoxic T-lymphocytes-associated protein 4 and programmed cell death protein-1, and the subsequent introduction of immune checkpoint inhibitors (ICIs) have revolutionized the treatment and prognosis of several cancers.
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