Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma
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Lijun Shi1, Yang Zhang2, Lin Feng1, Liming Wang2, Weiqi Rong2, Fan Wu2, Jianxiong Wu2, Kaitai Zhang1, Shujun Cheng1
1State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Shujun Cheng, email: firstname.lastname@example.org
Kaitai Zhang, email: email@example.com
Jiangxiong Wu, email: firstname.lastname@example.org
Keywords: spatial heterogeneity, tumor-infiltrating lymphocytes, gene expression profiling, somatic mutation, next generation sequencing
Received: December 21, 2016 Accepted: March 17, 2017 Published: March 31, 2017
Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor’s spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matched adjacent normal tissues and peripheral blood from five PLC patients. A significantly higher cumulative frequency of the top 250 most abundant TIL clones was observed in tumors than in peripheral blood. Besides, overlap rates of T cell receptor (TCR) repertoire for intratumor comparisons, significant higher than those for tumor-adjacent normal tissue comparisons and tumor-blood comparisons, which provide evidence for antigen-driven clonal expansion in PLC. Analysis of the percentage of ubiquitous TCR sequences, regional frequencies of each clone and TIL diversity suggested TIL clones varying between distinct regions of the same tumor, which indicated weak TCR repertoire similarity within a single tumor. Furthermore, correlation analysis revealed that TIL diversity significantly correlated with the expression of immune response genes rather than the mutation load. We conclude that intratumoural T-cell clones are spatially heterogeneous, which can lead to underestimate the immune profile of PLC from a single biopsy sample and may present challenge to adoptive cell therapy using autologous TILs. TIL diversity provides a reasonable explanation for the degree of immune response, implied TIL diversity can serve as a surrogate marker to monitor the effect of immunotherapy.
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