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Thomas Flaig, MD


Biological Mechanisms Behind Immune Checkpoint Inhibitors in Bladder Cancer

By: Amy MacDonald, MS
Posted: Monday, October 16, 2023

Jeroen van Dorp, MD, and Michiel van der Heijden MD, PhD, of the Netherlands Cancer Institute, Amsterdam, authored a comprehensive review of immune checkpoint inhibitor use in patients with bladder cancer. Their article, published recently in Frontiers in Immunology, meticulously catalogs immune checkpoint inhibitor use thus far in bladder cancer and attempts to tease out the role of individual immune cells in the bladder tumor microenvironment.

“It is becoming apparent that treatment with [immune checkpoint inhibitors] is not a one-size-fits-all treatment, but its efficacy is instead highly dependent on characteristics of the tumor and the tumor immune microenvironment,” the authors explained. “The mechanism of action of [immune checkpoint inhibitors] is complex and dependent on preexisting factors in the tumor microenvironment such as the abundance and activation state of CD8-positive T cells, the presence of other immune cells, and local cytokine signaling. In addition, treatment with [immune checkpoint inhibitors] directly influences and changes the tumor microenvironment, resulting in a delicate interplay,” they continued.

The authors’ review offers a comprehensive listing of completed and ongoing clinical trials for patients with bladder cancer in which either anti-CTLA-4 and/or anti–PD-L/PD-L1/2 immune checkpoint inhibitors have been studied. In addition, they discussed the potential roles of many immune factors such as tumor mutational burden, tumor genomic alterations, CD8-positive T cells, CD4-positive T cells, the immunologic “heat” of a tumor, macrophages, dendritic cells, natural killer cells, eosinophils, and even tertiary lymphoid structures.

The authors concluded that the process of antitumor immunity in bladder cancer is complex and dynamic. Although the importance of TGF-beta signaling, the role of CD4-positive T cells, and high-dose CTLA-4 inhibition (used together with PD-1/PD-L1 inhibition) may be important in immune checkpoint inhibitor treatment of bladder cancer, more research is required.

Disclosure: For full disclosures of the study authors, visit

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