Heterogeneity of tumor-infiltrating lymphocytes ascribed to local immune status rather than neoantigens by multi-omics analysis of glioblastoma multiforme

Abstract

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.

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer

“…Several studies have used TCR sequencing to examine the intratumoral T cell response in solid cancers [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25], including in NSCLC [10,26,27]. TCR repertoire analysis has also been used as a biomarker, in the context of checkpoint blockade [28,29,30,31,32,33,34,35].…”

Immunogenetics of glioblastoma: the future of personalized patient management

“… 63 In several cancers, T cell diversity has been shown to correlate with mutational burden in the tumor 6 ; however, a recent study in GBM contradicts this finding. 64 Specifically, this study reports the local environment as the major source of heterogeneity contributing to T cell diversity, and the authors suggest that tumor-specific neoantigens may not stimulate lymphocyte activation in GBM as they do in other tumor types. 64 As such, it remains unclear whether the identification of cancer-specific antigens and tumor-reactive T cell clonotypes has therapeutic potential in glioma.…”

High Somatic Mutation and Neoantigen Burden Do Not Correlate with Decreased Progression-Free Survival in HCC Patients not Undergoing Immunotherapy

“…Indeed, tumor infiltrating lymphocytes (TILs) not only have been shown to be mostly directed towards neoantigens, but their frequency correlates to the tumor mutational burden and patients' survival across a range of tumor types [3,[8][9][10][11][12]. However, contradictory results have been recently reported about correlation of the neoantigen load with the patients' survival in other tumors [13][14][15][16]. Moreover, the number of predicted neoantigens correlates with clinical outcomes in melanoma and lung cancer patients undergoing anti-CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) or anti-PD-1 (Programmed cell death protein 1) immune checkpoint blockade antibody therapy [17][18][19].…”