Transcriptomic analysis of more than 100 metastatic renal cell carcinomas (mRCC) has revealed key differences in aberrant alternative gene splicing events between treatment responders and nonresponders that could aid prognostication in future.
“In the near term, these findings could help guide treatment selection by identifying patients more likely to respond to targeted therapies or standard immuno-oncology regimens,” said Patrick Pirrotte, PhD, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, associate professor in TGen’s Early Detection and Prevention Division, and senior author of the paper.
“Longer term, splicing-derived antigens could provide a foundation for more personalized adoptive immunotherapy strategies tailored to the molecular features of an individual patient’s tumor,” he told Inside Precision Medicine.
Pirrotte explained that “alternative splicing [AS] is a fundamental transcriptional mechanism that expands proteomic diversity in normal cells, but aberrant splicing is increasingly recognized as a feature of cancer that can contribute to tumorigenesis, progression, and metastasis.”
His group, and collaborators, have previously demonstrated that aberrant splicing could act as a broadly relevant biomarker across different malignancies, including ovarian cancer and sarcomatoid renal cell carcinoma, but its diagnostic and predictive potential in mRCC remained largely unexplored.
To address this, Pirrotte and team conducted a retrospective analysis on tumor samples from 101 patients with mRCC who received immune checkpoint inhibitor (n=91) and/or targeted (n=77) therapies. Response rates to each of the therapies were 63% and 77%, respectively.
The researchers report in the Journal for ImmunoTherapy of Cancer that they identified 10 AS events that were specific to mRCC. Six of these were intron retention events and four were exon skipping events.
Differential AS analysis identified 461 slicing events that differed between responders and non-responders to immune checkpoint inhibitors and 253 events that differed between targeted therapy responders and non-responders. In both cases, more than 70% of novel AS events among responders involved intron retention.
“Intron retention was the predominant alternative splicing event observed in patients who responded well to therapy,” observed Pirrotte.
“Mechanistically, intron retention occurs when intronic sequences that are normally removed during RNA processing are retained in the mature transcript. This can generate novel amino acid sequences and, in some cases, tumor-associated antigens derived from aberrant splicing,” he explained. “A high intron-retention burden was associated with an immunogenic tumor microenvironment, marked by adaptive immune activation and enriched antigen processing. In simple terms, these cancer-specific splicing errors may help ‘flag’ tumor cells, making them more visible to the immune system.”
The team then investigated whether differentially spliced sequences shared between the immunotherapy and targeted therapy responder cohorts could potentially act as neoantigenic targets.
This revealed that novel peptide-generating AS events in the genes IFFO1 and ZNF692 were highly expressed among the responders. Both genes are known to play a role in tumorigenesis and metastasis in RCC and colorectal cancer. The researchers note that although the specific impact of AS events within these genes is unclear, the resulting neoantigens could play a role in future treatment approaches.
“It is becoming increasingly feasible to identify splicing-derived neoantigens that could be used in personalized immunotherapy approaches, including adoptive cell therapies such as CAR T-cell or tumor-infiltrating lymphocyte therapies,” said Pirrotte. “These strategies are designed to train or redirect a patient’s immune system to recognize tumor-specific antigen signatures. In this case, the targets would be antigens generated by aberrant splicing events, allowing immune cells to selectively recognize and kill cancer cells.”
Finally, the investigators showed that tumors with higher levels of aberrant splicing were more common among therapy responders than nonresponders. This could potentially be used as a biomarker for treatment response.
“Current biomarkers such as PD-L1 expression and microsatellite instability have shown limited and inconsistent predictive value in mRCC,” said Pirrotte. “In contrast, our study identified a significant association between tumor ‘splicing burden’ (the extent of aberrant splicing) and clinical response to therapy. These findings suggest that the tumor transcriptome, particularly splicing dysregulation, may provide a more informative framework for predicting treatment response and personalizing therapy.”
Before assessment of AS can be implemented in routine clinical practice, the core technologies will need further refinement, including clinically validated RNA sequencing workflows, robust computational pipelines for splicing analysis, and clear regulatory and technical frameworks for using the results to guide treatment decisions or develop biologic therapies.
Pirrotte and team are now assembling validation cohorts to confirm their findings in larger patient populations. They are also expanding their work to other cancer types to determine whether aberrant splicing and splicing-derived antigens represent broadly applicable biomarkers and therapeutic targets.
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