تقرير
Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer
| العنوان: | Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer |
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| المؤلفون: | Memon, Danish, Rizvi, Hira, Fromm, George, Lihm, Jayon, Schoenfeld, Adam J., Sauter, Jennifer L., Luo, Jia, Chow, Andrew, Bhanot, Umesh K., McCarthy, Caroline, Ye, Darwin, Vanderbilt, Chad M., Liu, Cailian, Abu-Akeel, Mohsen, Plodkowski, Andrew J., McGranahan, Nicholas, Luksza, Marta, Greenbaum, Benjamin D., Merghoub, Taha, Minn, Andy J., Beltrao, Pedro, id_orcid:0 000-0002-2724-7703, Schreiber, Taylor H., Miller, Martin L., Hellmann, Matthew D. |
| المصدر: | bioRxiv |
| بيانات النشر: | Cold Spring Harbor Laboratory |
| سنة النشر: | 2021 |
| المجموعة: | ETH Zürich Research Collection |
| الوصف: | Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance. |
| نوع الوثيقة: | report |
| وصف الملف: | application/application/pdf |
| اللغة: | English |
| العلاقة: | http://hdl.handle.net/20.500.11850/531958Test |
| DOI: | 10.3929/ethz-b-000531958 |
| الإتاحة: | https://doi.org/20.500.11850/531958Test https://doi.org/10.3929/ethz-b-000531958Test https://doi.org/10.1101/2021.07.21.452854Test https://hdl.handle.net/20.500.11850/531958Test |
| حقوق: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0Test/ ; Creative Commons Attribution 4.0 International |
| رقم الانضمام: | edsbas.48871C8E |
| قاعدة البيانات: | BASE |
| DOI: | 10.3929/ethz-b-000531958 |
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