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Thomas Flaig, MD


Strategies for Reversing Treatment Exhaustion in Immunologically Nonresponsive Urothelial Carcinoma

By: Amy MacDonald, MS
Posted: Wednesday, August 2, 2023

Although immune checkpoint therapies have been approved for treatment of advanced urothelial carcinoma, strategies are needed to improve the efficacy of these immunotherapies, since they may not be superior to traditional platinum-based therapy in some patients. It has been observed that radiation therapy may alter the immune environment outside the immediate irradiation field in some tumors (termed the abscopal effect). This alteration may be beneficial in reducing tumors outside the radiation field.

Minoru Kato, MD, PhD, of Osaka Metropolitan University, Japan, and colleagues hoped to investigate the abscopal phenomenon in urothelial carcinoma to determine whether it could be harnessed to augment immune checkpoint therapy. The researchers determined that regulating specific immune cells (myeloid-derived suppressor cells) in combination with radiation therapy may overcome treatment failure in vitro and in vivo in mouse bladder cancer models. Their research was published in the British Journal of Cancer.

The researchers performed a variety of in vitro experiments using the established MB49 bladder cancer cell line as well as a cisplatin-resistant version, MB49R. Numerous in vivo experiments were also performed in mice. Immune cell infiltration into tumors was evaluated using subcutaneous, lung, liver, and bone metastases.

To explore whether CD8-positive T cells were required for PD-L1 inhibitors to function in bladder tumors with few CD8-positive T cells, MB49R cells were inoculated subcutaneously into mice. When the tumors reached palpability, the mice were treated with anti–PD-L1 antibodies. Finally, the effect of blocking myeloid-derived suppressor cells (with or without radiation therapy) was evaluated using MB49 and MB49R cells in a mouse xenograft model.

The researchers concluded that the combination of radiation therapy (with myeloid-derived suppressor cell-targeted therapy) effectively mitigated resistance to immune checkpoint therapy in “immunologically cold” tumors in murine models. They suggested that additional preclinical studies are warranted.

Disclosure: The study authors reported no conflicts of interest.

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