Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer accounting for 80% of all renal cancers as well as the majority of renal cancer-associated deaths. During the last decade, the treatment paradigm for ccRCC has radically changed. In particular, the recent development of immune checkpoint inhibitors (ICI) has led to an increased overall survival in the metastatic setting. Moreover, novel immune therapies targeting the tumor microenvironment have been developed. In this rapidly evolving treatment landscape, precise tools for personalized cancer therapy are needed. Here, we collected fresh tissue from 42 patients who underwent surgical resection for renal cell carcinoma. Part of the tissue was used to obtain formalin-fixed, paraffin-embedded samples or RNA. The remaining tissue was minced and cultured in a collagen-based three-dimensional, air-liquid interface (ALI) culture system. The generated patient-derived tumor organoids (ALI PDOs) were characterized by immunohistochemistry staining and RNA sequencing to validate their close similarity to the matched tumor. Immune cells and stromal cells within the microenvironment could be identified. Finally, we treated 10 ALI PDOs with the commonly used targeted cancer drug cabozantinib or the ICI nivolumab. Interestingly, we observed varying responses of ALI PDOs to these treatments and future studies are needed to investigate whether the ALI PDO approach could inform about treatment responses in patients. In conclusion, this three-dimensional ccRCC culture model represents a promising, facile tool for monitoring tumor responses to different types of therapies in a controlled manner, yet, still preserves the key features of the tumor of origin.
Highlights
MATERIALS AND METHODSRenal cancer affected about 403,300 people and led to approximately 175,000 deaths globally in 2018 [1]
The objective response rate of PD-L1 positive tumors was 55.2% compared to 51.4% in the overall cohort, which indicates that PD-L1 expression is not a reliable predictor for therapy response in renal cell carcinoma (RCC) [9]
Neal and colleagues established a protocol to cultivate patient-derived organoids (PDOs) in an air-liquid interface (ALI) system, which sustains the complex structure of the tissue of origin [16]
Summary
Renal cancer affected about 403,300 people and led to approximately 175,000 deaths globally in 2018 [1]. Patient-derived organoids (PDOs) from many different tumor types have been established and gained interest as a tool for drug screening [10,11,12]. Only a few studies using patient-derived material such as primary cell lines or tumor (stem) cellderived organoids have been published with regard to drug testing [13,14,15]. We used the protocol of Neal and colleagues to cultivate 42 air-liquid interface patient-derived organoids (ALI PDOs) from renal tumors, characterized them by different approaches and examined the treatment response to cabozantinib and nivolumab. Passaging of ALI PDOs was performed by addition of 200 units ml−1 collagenase IV to the insert and incubation for 30 min at 37◦C until the collagen was dissociated. In case of no decrease in viability, no response was indicated (“–“), up to 1/3 reduction in viability was indicated as a weak response (“+”), up to 2/3 reduction as a medium response (“++”), and more than 2/3 reduction as a strong response (“+++”)
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