| Autor: |
Richard Chen, Sekwon Jang, Michael P. Snyder, Rena McClory, Jason Harris, Gabor Bartha, Pamela Milani, Zeid M. Rusan, Rose Santiago, Mengyao Tan, Simo V. Zhang, Dattatreya Mellacheruvu, Fábio C.P. Navarro, Eric Levy, Lee D. McDaniel, Rachel Marty Pyke, Sean M. Boyle, Charles W. Abbott |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6530534 |
| Popis: |
Purpose:While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB).Experimental Design:Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB.Results:Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002).Conclusions:NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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