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

https://doi.org/10.1016/j.urolonc.2017.04.007Get rights and content

Highlights

  • Therapeutic blockade of PD-L1 can lead to durable remissions in advanced bladder cancer.

  • There are newly described immune checkpoints including B7-H3, B7x, and HHLA2.

  • Blocking these receptors may lead to immune-mediated urothelial tumor eradication.

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.

Section snippets

Historical perspective of immunotherapy for bladder cancer

The first suggestion of interplay between tumor biology and host immunity was in the 19th century when William Coley observed that infections were associated with tumor regression [1]. This antineoplastic effect of concomitant infection was again observed by Raymond Pearl at Johns Hopkins in 1929. He performed autopsies on patients who died of tuberculosis and noticed that there was a surprisingly low rate of underlying malignancy in these patients [2]. Alvaro Morales was the first to introduce

Overview of immune checkpoint receptors and pathways

Immune evasion is considered to be one of the hallmarks of cancer and is an essential step in the evolution of a tumor [13]. Tumor-immune evasion is achieved through multiple mechanisms: (1) selective evolution of tumors with down-regulated expression of neoantigens; (2) decrease or loss of expression of class I MHC molecules; (3) resistance to T-cell–mediated cytolytic killing; (4) presence of immune suppressing cells—regulatory T cells (T regs), myeloid-derived suppressor cells (MDSCs), and

Bladder tumors as immunogenic targets

Bladder cancers express high levels of PD-L1 [21]. Inman et al. demonstrated PD-L1 expression in bladder tumors of all stages, with particularly high levels in advanced stage tumors (30%) and tumors with carcinoma in situ (CIS) (45%). Furthermore, PD-L1 expression was abundant in tumors refractory to BCG treatment, suggesting that PD-L1 may play a role in shielding the tumor from immune-mediated tumor destruction. Boorjian et al. [22] observed that increased PD-L1 expression was associated with

Clinical trials of checkpoint inhibitors in urothelial carcinoma

Until 2016, there had been no new systemic treatments for advanced urothelial carcinoma approved by the FDA in 3 decades [12]. Recent clinical trials have demonstrated considerable therapeutic benefit of anti-CTLA-4 and anti-PD-1/PD-L1 agents in metastatic melanoma [24], [25], [26], leading to durable clinical remissions in an otherwise incurable disease.

The first phase I study of an anti-PD-L1 antibody (atezolizumab) in urothelial carcinoma was reported by Powles et al. [27]. Study

New immune checkpoints B7-H3, B7x, and HHLA2

The evolution of the B7 family members can be divided into 3 groups based on amino acid similarity. B7-H3 [35], B7x [36], [37], [38], and HHLA2 [39] form the third group of molecules [36] (Fig. 3). These molecules are widely expressed in many urologic malignancies, and their expression is associated with a poor prognosis [22], [40]. Tumor cell surface overexpression of these ligands is thought to play an essential role in suppressing T-cell response, leading to immune tolerance of malignancies.

Summary

The understanding of the regulation of T-cell activation and function along with the discovery of immune checkpoints with respect to the CD28 and B7 family has led to major advances scientifically and therapeutically in cancer. Clinical trials of agents targeting the PD-L1 checkpoint pathway have demonstrated durable clinical remissions in patients with otherwise untreatable advanced bladder cancer. Future studies should aim to further characterize the role of the newest B7 family molecules

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    A.S. is a consultant and advisor for Genentech. M.P.S. is an investor and consultant for Urogen.

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