Feng et al. performed whole-exome sequencing, gene expression analysis, and TCR sequencing on multiple regions from two spatially separated tumor samples from a glioblastoma multiforme (GBM) patient, and found that the TCR clonal diversity was not related to the distribution of neoantigens, and instead correlated with locally activated immune pathway genes. Expression signatures of 23 of these genes in 50 GBM patients stratified prognosis.

Hypothetically, intratumoral genomic heterogeneity has the potential to foster tumor-infiltrating lymphocyte (TIL) diversity; however, no study has directly tested this hypothesis by simultaneously investigating somatic mutations, TIL diversity, and immune response activity. Thus, we performed whole-exome sequencing, immune repertoire sequencing and gene expression on ten spatially separated tumor samples obtained from two tumor masses excised from a glioblastoma multiforme (GBM) patient, and we included peripheral blood as control. We found that although the multi-region samples from one tumor shared more common mutations than those from different tumors, the TIL populations did not. TIL repertoire diversity did not significantly correlate with the number of non-synonymous mutations; however, TIL diversity was highly correlated with local immune activity, as the pathways were all immune-related pathways that highly positive correlated with local TIL diversity. Twenty-three genes with expression largely unaffected by the intratumor heterogeneity were extracted from these pathways. Fifty GBM patients were stratified into two clusters by the expression of these genes with significant difference in prognosis. This finding was validated by The Cancer Genome Atlas (TCGA) GBM dataset, which indicated that despite the heterogeneity of intra-tumor immune status, the overall level of the immune response in GBM could be connected with prognosis.

Author Info: (1) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (2) Department of Neurosurgery, National C

Author Info: (1) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (2) Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (3) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150008, China. (4) Department of Diagnostic Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (5) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (6) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (7) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (8) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (9) Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. lixji@126.com. (10) Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. wanjinghai@sina.com. (11) National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. zhangkt@cicams.ac.cn.