Gene Editing Yields Immune-Competent Model for Studying BAP1-Deficient Melanoma

A research team at the University of Turku has developed a laboratory model to study BAP1-deficient melanomas, a rare and aggressive type of melanoma that evades the immune system and is universally resistant to current immunotherapies. The study was published in Communications Biology.

BAP1-deficient melanoma is the most common intraocular malignancy in adults, but it remains rare and extremely difficult to treat once it spreads. When the disease metastasizes to the liver, which occurs in roughly half of patients, median survival is measured in months. Unlike more common melanomas, BAP1-deficient tumors do not respond to immune checkpoint therapies. The central driver of this resistance is the loss of a gene called BAP1 (BRCA1-associated protein 1). When BAP1 is lost, tumors become more aggressive, grow faster, and suppress the immune cells that would otherwise attack them. BAP1 loss is also implicated in mesothelioma, renal cell carcinoma, and other cancers.

Despite its clinical significance, the consequences of BAP1 loss have been difficult to study in the laboratory. No suitable immune-competent model existed—previous models either lacked a functional immune system, making them unsuitable for immunotherapy research, or carried too many confounding mutations that obscured the specific role of BAP1.

To fill this gap, the team used CRISPR-Cas9 gene editing to delete BAP1 from normal melanocyte cells, creating a preclinical tumor model that behaves like human BAP1-deficient melanoma in an animal with a fully functioning immune system. 

“BAP1 loss is associated with poor prognosis and resistance to immunotherapy in melanoma. Until now, there has been no preclinical model that faithfully reproduces the tumor–immune interactions seen in patients. Our model fills this gap, for the first time, by recapitulating the human tumor immune microenvironment in vivo. This provides a powerful platform to study how BAP1 loss drives immune evasion and to test novel immunotherapy combinations that may overcome treatment resistance,”" said first author Mona Wang Meng.

The researchers emphasize that the model's applications extend beyond melanoma. “The implications go well beyond melanoma. BAP1 loss is a shared vulnerability across several hard-to-treat cancers. This platform allows us, and research groups worldwide, to rationally design and test new immunotherapy combinations—something that simply was not possible before,” said Carlos R. Figueiredo, the study’s principal investigator.