The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1

Abstract

Over the last decade, a new understanding of tumor-immune system interplay has been ushered in, lead in large part by the discovery of immune checkpoints mediated through B7-CD28 family interactions. Therapeutic blockade of the PD-L1 immune checkpoint pathway has already shown great success as a cancer immunotherapy for advanced urothelial carcinoma, leading to durable clinical remissions in an otherwise incurable disease. There are newly described members of the B7-CD28 family including B7-H3, B7x, and HHLA2. These ligands are thought to play an essential role in suppressing T-cell response, leading to immune tolerance of tumors. This feature makes them attractive targets for novel immunotherapy treatment paradigms. Here, we review the literature of current strategies and future directions of immune checkpoint blockade therapy for bladder cancer.

Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial

“…6,7 Recently, checkpoint inhibitors have altered the treatment of mUC. 8 Pembrolizumab, an anti-programmed death-1 (PD-1) agent, demonstrated longer survival over chemotherapy in mUC in a randomised phase 3 trial. 9 Additionally, atezolizumab-a monoclonal antibody that inhibits programmed death-ligand 1 (PD-L1) while leaving the PD-L2/PD-1 interaction intact 10,11 -is active and well tolerated across multiple cancers, including mUC.…”

BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer

“…Cancer cells can evade the immune response by the expression of different checkpoint proteins, including CTLA-4, PD-L1, and PD-L2. In fact, a number of clinical trials targeting these membrane proteins in urothelial cancer have already shown promising results (44). Importantly, these socalled immune checkpoints are also expressed in nontumoral cells, including TAMs (45).…”

Human endogenous retrovirus-H long terminal repeat-associating 2: The next immune checkpoint for antitumour therapy

“…Given that numerous studies separately discovered unfavourable prognosis correlated to HHLA2 expression across multiple human cancers, there was a long-held estimation that an unidentified co-inhibitory receptor of HHLA2 was expressed on activated T cells which HHLA2 on tumour cells or APCs could interact with to protect tumours form immune surveillance. 64 , 65 , 66 , 67 …”