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Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

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.

SUBMITTER: Lu T

PROVIDER: S-EPMC7239327 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Lu Tianshi T Wang Shidan S Xu Lin L Zhou Qinbo Q Singla Nirmish N Gao Jianjun J Manna Subrata S Pop Laurentiu L Xie Zhiqun Z Chen Mingyi M Luke Jason J JJ Brugarolas James J Hannan Raquibul R Wang Tao T

Science immunology 20200201 44

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 stud ...[more]

PMID: 32086382

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Project description:Despite the recent increase in the use of immune checkpoint blockade (ICB), no ICB medications have been approved or are undergoing large-scale clinical trials for glioma. T cells, the main mediators of adaptive immunity, are important components of the tumor immune microenvironment. Depletion of T cells in tumors plays a key role in assessing the sensitivity of patients to immunotherapy. In this study, the bioinformatics approach was applied to construct T cell depletion-related risk assessment to investigate the impact of T cell depletion on prognosis and ICB response in glioma patients. The Cancer Genome Atlas (TCGA) and GSE108474 glioma cohorts and IMvigor210 immunotherapy datasets were collected, including complete mRNA expression profiles and clinical information. We used cell lines to verify the gene expression and the R 3.6.3 tool and GraphPad for bioinformatics analysis and mapping. T cell depletion in glioma patients displayed significant heterogeneity. The T cell depletion-related prognostic model was developed based on seven prognostic genes (HSPB1, HOXD10, HOXA5, SEC61G, H19, ANXA2P2, HOXC10) in glioma. The overall survival of patients with a high TEXScore was significantly lower than that of patients with a low TEXScore. In addition, high TEXScore scores were followed by intense immune responses and a more complex tumor immune microenvironment. The "hot tumors" were predominantly enriched in the high-risk group, which patients expressed high levels of suppressive immune checkpoints, such as PD1, PD-L1, and TIM3. However, patients with a low TEXScore had a more significant clinical response to immunotherapy. In addition, HSPB1 expression was higher in the U251 cells than in the normal HEB cells. In conclusion, the TEXScore related to T cell exhaustion combined with other pathological profiles can effectively assess the clinical status of glioma patients. The TEXScore constructed in this study enables the effective assessment of the immunotherapy response of glioma patients and provides therapeutic possibilities.

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Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Publications

Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

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