Response Stratification in the First-Line Combined Immunotherapy of Hepatocellular Carcinoma at Genomic, Transcriptional and Immune Repertoire Levels
| Autor: | Jianfei Yao, Lele Song, Zheng Dong, Yan Chen, Aifang Ge, Zhen Zeng, Xiaohui Wang, Jiagan Huang, Rui Zhang, Yinyin Li, Jiamin Cheng, Xueyuan Jin, Yinying Lu |
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| Rok vydání: | 2021 |
| Předmět: |
Sorafenib
medicine.medical_treatment mRNA lenvatinib Biology Gene mutation chemistry.chemical_compound lncRNA TIGIT medicine HCC Journal of Hepatocellular Carcinoma Original Research sintilimab T-cell receptor Immunotherapy hepatocellular carcinoma medicine.disease chemistry Hepatocellular carcinoma PFKP Cancer research sorafenib immunotherapy Lenvatinib TCR medicine.drug |
| Zdroj: | Journal of Hepatocellular Carcinoma |
| ISSN: | 2253-5969 |
| Popis: | Jiamin Cheng,1,* Yinyin Li,1,* Xiaohui Wang,2,* Zheng Dong,1 Yan Chen,1 Rui Zhang,1 Jiagan Huang,1 Xueyuan Jin,1 Jianfei Yao,2 Aifang Ge,2 Lele Song,2,3,* Yinying Lu,1 Zhen Zeng1 1Comprehensive Liver Cancer Department, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, 100039, Peopleâs Republic of China; 2HaploX Biotechnology, Shenzhen, Guangdong Province, Peopleâs Republic of China; 3Department of Radiotherapy, The Eighth Medical Center of the Chinese PLA General Hospital, Beijing, 100091, Peopleâs Republic of China*These authors contributed equally to this workCorrespondence: Yinying Lu; Zhen ZengComprehensive Liver Cancer Department, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, 100039, Peopleâs Republic of ChinaEmail luyinying1973@163.com; zengzhen1970@sina.comBackground: Immunotherapy combined with VEGF inhibitor has become the new first-line therapy for advanced or metastatic hepatocellular carcinoma (HCC). However, the biomarkers for response and prognosis stratification of HCC first-line combined immunotherapy have not been clarified.Methods: Here, we obtained the genomic alteration data from pre-therapeutic samples of 103 HCC patients using a 605-gene NGS test, and obtained the transcriptional and T cell receptor (TCR) diversity data from 18 patients who underwent the first-line combined immunotherapy using RNAseq and TCR sequencing, respectively. Patients received sorafenib/sintilimab or lenvatinib/sintilimab combined first-line therapy and the response was assessed at 3â 6 cycles of therapy.Results: No stratification of response was found in high-frequency key driver gene mutations, including TP53 and TERT. However, significantly higher ratio of progression (PD) was found in patients carrying MDM4 amplification. Similarly, FGF/3/4/19 amplifications could also result in high ratio of PD. The mRNA and lncRNA levels of eight genes related to hepatic metabolism and immune microenvironment exhibited significant differences between PR/SD and PD group, including DGKI, TNFSF14, CHST4, ACTIN1, PFKP, SLC51B, LCK and ERN1, suggesting stratification of response. Furthermore, moderate correlation was identified between the stratification genes (CHST4, SLC51B and ERN1) and immune factors (TIGIT, CD34, ICAM1, CCL5, CXCL9 and CXCL10), suggesting potential roles of these factors in immunoregulation. Strong linear correlation was found between any two of the three indexes for TCR CDR3 diversity, including ShannonâWiener Index, Simpson index and evenness. However, no significant difference was found in the three indexes between the PR/SD and PD group, suggesting no stratification of response by these indexes.Conclusion: We identified several potential biomarkers for response stratification in the first-line combined immunotherapy. MDM4 was capable of predicting disease progression, and a panel mRNA and lncRNA of eight genes may also predict the response. Further validation is needed to verify these biomarkers.Keywords: hepatocellular carcinoma, HCC, immunotherapy, mRNA, lncRNA, TCR, sintilimab, sorafenib, lenvatinib |
| Databáze: | OpenAIRE |
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