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.

The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2

“…1a ). As there are currently no well-accepted tools for predicting the potential of both class I and II epitopes to induce T cell responses, we used the binding affinity of epitopes to MHCs as a surrogate for epitope immunogenicity, since such binding affinity has been shown to be one of the most important predictors of epitope immunogenicity ( Lu et al, 2020b ). As this virus was initially reported in China, the counts of the MHC binders for the reference genome were weighted by the allele frequencies of the Chinese population.…”

DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

“…Thus, further exploration and refinement of NER and HR gene mutation panels and testing of their use in combination with existing and emerging biomarkers, including algorithms that assess the clonality and immunogenicity of neoantigens, may yield more powerful predictors of ICI activity across many cancer types. 35 …”

The Neoantigen Landscape of Mycosis Fungoides

“…CSiN combines neoantigen load, neoantigen clonality and immunogenicity in a single score and is believed to reflect the sensitivity of the tumor to immunotherapy (40). We used transcripts per million (TPM) counts calculated by Kallisto (30) FIGURE 1 | Summary of methods and study design.…”

“…The Cauchy-Schwarz index of Neoantigens (CSiN) reduces the number of neoantigens, their clonality and immunogenicity in the sample to a single number (40). CSiN has been argued to out-perform existing metrics as a biomarker of tumor immunogenicity and response to immune checkpoint inhibitors across different neoplasms (40). The CSiN scores of our samples are shown in Figure 5C.…”