Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer

Qingzhu Jia,Wei Wu,Haidong Wang,Qi-Jing Li,Yuqi Wang,Yisong Y Wan,Jia-Nan Cheng,Zhihua Gong,Ling Yang,Xin Yi,Chengdu Sun,Huaibo Sun,Ji He,Xuefeng Xia,Yanfang Guan,Peter B Alexander,Bo Zhu,P Andrew Futreal

doi:10.1038/s41467-018-07767-w

Abstract

Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy.

Highlights

IntroductionTranscriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC)
Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC)
When we assessed programmed death-ligand 1 (PD-L1) expression, which is known to be upregulated upon IFN stimulation[34] and serves as a biomarker for patient stratification for anti-PD1 immunotherapy[3], we found that both messenger RNA and protein levels of PD-L1 were heterogeneous among different tumor loci and did not correlate with local total mutational burden (TMB) (Fig. 2g and Supplementary Fig. 8)

Summary

Introduction

Transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy. It suggests that the accurate identification of candidates for immunotherapy might be improved by more comprehensively measuring local tumor attributes, in comparison to solely focusing on TMB or neoantigen load as is the current practice

Methods

Results

Conclusion