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Published on: November 5, 2019
[A method of screening highly common neoantigens with immunogenicity in colorectal cancer based on public somatic
Li Li Qin1,2, Yi Jian Li1, Zhao Rui Liang1
1BGI-Shenzhen, Shenzhen 518083, China.
Abstract:
Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to personalized precision therapy, due to the individual differences of unique neoantigens. With the discovery of many common oncogenic mutations, and such mutation-associated neoantigens could cover more patients, and hence are valuable in clinical field. However, whether the common neoantigens can be identified in CRC is unknown. Combining the somatic mutations data from 321 CRC patients with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*1101-restricted common neoantigens with a high binding affinity (IC50<50 nmol/L) and presentation score (>0.90). Besides the positive epitope KRAS_G12V8-16, 11 out of 25 common neoantigens specifically induced in vitro pre- stimulated cytotoxic lymphocyte (CTL) to secrete interferon gamma (IFN-γ). Moreover, combining cell-sorting technology and single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 and KRAS_G12V8-16-specific CTL were analyzed and validated. Their related T-cell receptor engineered T cell (TCR-T) cells could also recognize the neoantigens and secrete IFN-γ. Hence, we have established a method to screen for common neoantigens with immunogenicity in CRC based on the public somatic mutation library. It can provide essential peptide and TCR information for immunotherapies, such as peptides, dendritic cells (DC) vaccines, TCR-like antibodies, TCR-T, etc., for the CRC and other cancers, which has practical application value in the clinics.
Insights
Researchers identified 25 common neoantigens in colorectal cancer (CRC) that can trigger immune responses. This discovery offers potential for developing broader immunotherapies beyond personalized treatments for CRC and other cancers.
Area of Science:
- Oncology
- Immunology
- Bioinformatics
Background:
- Colorectal cancer (CRC) presents significant global health challenges due to high incidence and mortality.
- Current neoantigen-based immunotherapies are largely personalized, limiting their broad applicability.
- Identifying common neoantigens associated with frequent mutations could expand treatment accessibility.
Purpose of the Study:
- To investigate the feasibility of identifying common neoantigens in colorectal cancer.
- To screen for immunogenic common neoantigens in CRC patients.
- To establish a method for developing broadly applicable cancer immunotherapies.
Main Methods:
- Utilized somatic mutation data from 321 CRC patients.
- Applied a filtering standard and seven prediction algorithms to screen neoantigens.
- Validated immunogenicity using in vitro stimulated cytotoxic lymphocytes (CTLs) and analyzed immune repertoire profiles via single-cell RNA sequencing.
Main Results:
- Identified 25 HLA-A*1101-restricted common neoantigens with high binding affinity and presentation scores.
- Eleven of these neoantigens, including KRAS_G12V8-16, induced interferon-gamma (IFN-γ) secretion in CTLs.
- Validated T-cell receptor engineered T cells (TCR-T) targeting specific neoantigens (C1orf170_S418G413-421 and KRAS_G12V8-16) demonstrated recognition and IFN-γ secretion.
Conclusions:
- Developed a robust method for screening immunogenic common neoantigens in CRC using public mutation data.
- The identified neoantigens and associated T-cell receptor (TCR) information are valuable for developing peptide, dendritic cell (DC) vaccines, and TCR-T therapies.
- This approach holds significant clinical potential for CRC and other cancers, moving beyond solely personalized treatments.
