Emerging role of immunotherapy in urothelial carcinoma-Immunobiology/biomarkers

Abstract

Urothelial bladder cancer is one of the first cancers recognized to be immunogenic since 40 years ago when the use of bacillus Calmette-Guerin was shown to prevent recurrence. Since that time, our knowledge of immune biology of cancer has expanded tremendously, and patients with bladder cancer finally have new active immunotherapeutic drugs on the horizon. Anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) therapy has shown impressively durable responses in urothelial bladder cancer (UBC), but the reported response rates warrant improvement. To outline potential strategies to overcome tumor immune resistance, herein, we summarize current models of tumor immunology with a specific focus on bladder cancer. Recognition of tumor-specific antigens through cross-presentation, T-cell priming and activation, and trafficking of immune cells to the tumor microenvironment are some of the critical steps we now understand to be necessary for an effective antitumor immune response. Many of the involved steps are important targets for therapeutic interventions. As new immunotherapies are developed, predictive biomarkers would also be important to select patients most likely to respond and to better understand tumor biology. Several potential biomarkers are reviewed including PD-L1 expression, identification of T-cell-inflamed/non-T-cell-inflamed tumors based on immune gene expression, intrinsic molecular subtyping based on luminal/basal or the cancer genome atlas (TCGA) groups, T-cell receptor sequencing, and somatic mutational density. Even within the past few years, our current knowledge of immune biology has exploded, and we are highly optimistic about the future of UBC therapy that will be available to patients.

Keywords: Biomarkers; Bladder cancer; Immune checkpoint therapy; Immunology; Urothelial cancer.

Figure 1

Cumulative number of United States Food and Drug Administration (FDA) drug approvals in genitourinary cancers beginning in 1995 through 2015. Only a single drug, valrubicin, was approved for UBC during this time period.

Figure 2

Schema depicting the development of T cell-inflamed versus non-T cell-inflamed tumor microenvironments in UBC. T cell-inflamed tumors are associated with upregulation of immune inhibitory pathways that suppress the immune response and result in resistance to anti-PD-1/PD-L1 therapy. In contrast, non-T cell inflamed tumors lack infiltrating T cells, thus generally do not respond to immune checkpoint blockade. This group may require immune priming strategies (vaccines, chemotherapy, radiation therapy, etc.) or targeting of oncogenic pathways that are resulting in T cell exclusion.