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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma
Haichao Zhao1,2, Yifei Cheng1, Tiancheng Zhang1
1Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeting tumor-specific antigens represents a cornerstone of cancer immunotherapy, current approaches focus predominantly on mutation-derived neoantigens, which offer limited population coverage. Through an integrative analysis of multi-omics data from 279 HCC patients, we demonstrate that aberrant splicing (AS) events occur at a > 59-fold higher frequency than somatic mutations and generate substantially more immunogenic peptides with broader patient applicability (50.94% vs 4.40% population coverage). Focusing on AS transcripts, our stringent selection pipeline identified 34 neoantigens, prioritizing strong immunogenicity for effective vaccine development. Proof-of-concept in vivo experiments demonstrated the efficacy of mRNA vaccines encoding these neoantigens, resulting in significant tumor regression and enhanced intra-tumor infiltration of neoantigen-reactive T cells. We also address the challenge of transporter-associated antigen processing (TAP) deficiency in HCC by proposing the use of TAP-independent AS-derived neoantigens to circumvent immune evasion. Our findings establish AS as a promising source of neoantigens for off-the-shelf mRNA vaccines in HCC and underscore the need to overcome antigen-presentation barriers for effective immunotherapy.
Insights
Aberrant splicing events in hepatocellular carcinoma generate more immunogenic neoantigens than mutations. These aberrant splicing neoantigens show promise for developing broadly applicable mRNA vaccines against liver cancer.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Hepatocellular carcinoma (HCC) immunotherapy faces challenges with limited patient coverage from mutation-derived neoantigens.
- Targeting tumor-specific antigens is crucial, but current methods are insufficient for broad HCC treatment.
Purpose of the Study:
- To identify novel neoantigens from aberrant splicing (AS) events in HCC.
- To evaluate the immunogenicity and therapeutic potential of AS-derived neoantigens for HCC vaccines.
- To explore strategies to overcome antigen presentation challenges in HCC immunotherapy.
Main Methods:
- Integrative analysis of multi-omics data from 279 HCC patients.
- Identification and selection of 34 highly immunogenic neoantigens from AS transcripts.
- In vivo validation of mRNA vaccines encoding AS neoantigens in HCC models.
Main Results:
- Aberrant splicing events occur 59-fold more frequently than somatic mutations in HCC.
- AS-derived neoantigens offer significantly broader patient applicability (50.94%) compared to mutation-derived neoantigens (4.40%).
- mRNA vaccines encoding AS neoantigens demonstrated significant tumor regression and enhanced T cell infiltration in vivo.
Conclusions:
- Aberrant splicing is a rich source of immunogenic neoantigens for HCC immunotherapy.
- AS-derived neoantigens are suitable for developing off-the-shelf mRNA vaccines for HCC.
- Overcoming antigen presentation barriers, such as TAP deficiency, is essential for effective HCC immunotherapy using AS neoantigens.
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