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 (BCG) was shown to prevent recurrence. Since that time, our knowledge of immune biology of cancer has expanded tremendously, and bladder cancer patients finally have new active immunotherapeutic drugs with 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 anti-tumor immune response. Many of the involved steps are important targets for therapeutic interventions. As new immunotherapies are developed, predictive biomarkers will 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 (TCR) sequencing, and somatic mutational density. Within even 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.

PD-L1 expression in bladder cancer and metastasis and its influence on oncologic outcome after cystectomy

“…In addition to PD-L1, other potential biomarkers including state of the art molecular subtyping, in depth TCR sequencing, somatic mutational density quantification, and identification of T cell-inflamed/non-T cell-inflamed tumor microenvironments using immune gene expression profiling are currently under investigation with promising results [ 7 , 36 ], highlighting the complexity and dynamic changes of the antitumor immune response [ 13 ], with the necessity for combined biomarkers. Nevertheless, preliminary data suggested a significant relationship between PD-L1 expression, clinical outcome, radiation response and therapeutic response to immunotherapy in bladder cancer [ 2 , 9 , 28 , 37 ].…”

Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell‐free DNA results

“…Although these agents undoubtedly represent a major milestone in therapy for patients with mUC, response rates generally are <30% in unselected populations. In particular, patients with immunologically “cold” tumors are less likely to derive benefit from PD‐1/PD‐L1 inhibition …”

Unmasking molecular profiles of bladder cancer

“…BC is known as one of highly immunogenic cancer types [ 62 63 ], and cancer immunotherapies aimed to stimulate the body's immune system (e.g., BCG) have been utilized to treat BC patients [ 9 ]. In the last ten years, there have been continued drug developments on new classes of immune checkpoint inhibitors.…”