Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy
Tianshi Lu1, Shidan Wang1, Lin Xu1,2
1Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Abstract:
Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally. Neoantigen load has been linked with treatment response and prognosis in some studies but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to better account for the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike total neoantigen load determinations, CSiN incorporates the effect of both clonality and MHC binding affinity of neoantigens when characterizing tumor neoantigen profiles. By analyzing the clinical responses in 501 treated patients with cancer (with most receiving checkpoint inhibitors) and the overall survival of 1978 patients with cancer at baseline, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in patients with melanoma, lung cancer, and kidney cancer. CSiN score substantially outperformed prior genetics-based prediction methods of responsiveness and fills an important gap in research involving assessment of tumor neoantigen burden.
Insights
A new Cauchy-Schwarz index of Neoantigens (CSiN) score improves prediction of cancer immunotherapy response. This novel method considers neoantigen immunogenicity, outperforming previous approaches for melanoma, lung, and kidney cancers.
Area of Science:
- Oncology
- Immunology
- Computational Biology
Background:
- Checkpoint inhibitors are crucial in cancer immunotherapy, but patient response varies.
- Tumor neoantigens are key targets for immune response, yet their assessment is often oversimplified.
- Current methods focusing on total neoantigen load have inconsistent predictive power for treatment response.
Purpose of the Study:
- To develop a refined method for assessing tumor neoantigen profiles.
- To introduce the Cauchy-Schwarz index of Neoantigens (CSiN) score for improved prediction of immunotherapy outcomes.
- To evaluate the CSiN score's ability to predict treatment response and prognosis in cancer patients.
Main Methods:
- Developed the Cauchy-Schwarz index of Neoantigens (CSiN) score.
- CSiN incorporates neoantigen clonality and MHC binding affinity.
- Analyzed clinical responses in 501 cancer patients and overall survival in 1978 patients.
Main Results:
- CSiN scores significantly predict treatment response to checkpoint inhibitors.
- CSiN demonstrates predictive value for prognosis in melanoma, lung, and kidney cancers.
- The CSiN score substantially outperformed existing genetics-based prediction methods.
Conclusions:
- The CSiN score offers a more accurate assessment of tumor neoantigen burden.
- CSiN enhances the prediction of immunotherapy responsiveness and patient prognosis.
- This index addresses limitations in current neoantigen assessment for personalized cancer therapy.
