Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types
Abstract Background The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes (i.e., WNT/β-catenin) are known to mediate im...
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| Format: | Article |
| Language: | English |
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BMC
2020-10-01
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| Series: | Genome Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s13073-020-00787-6 |
| _version_ | 1819063519063048192 |
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| author | Riyue Bao Daniel Stapor Jason J. Luke |
| author_facet | Riyue Bao Daniel Stapor Jason J. Luke |
| author_sort | Riyue Bao |
| collection | DOAJ |
| description | Abstract Background The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes (i.e., WNT/β-catenin) are known to mediate immunosuppression. Methods We performed an integrated multi-omic analysis of human cancer including 11,607 tumors across multiple databases and patients treated with anti-PD1. After adjusting for TMB, we correlated the T cell-inflamed gene expression signature with somatic mutations, transcriptional programs, and relevant proteome for different immune phenotypes, by tumor type and across cancers. Results Strong correlations were noted between mutations in oncogenes and tumor suppressor genes and non-T cell-inflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c, and genes with unknown functions. Conversely, we observe genes associating with the T cell-inflamed phenotype including VHL and PBRM1. Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion across cancer types (HIF1A and MYC) as well as novel examples in specific tumors such as sonic hedgehog signaling, hormone signaling and transcription factors. Using network analysis, somatic and transcriptomic events were integrated. In contrast to previous reports of individual tumor types such as melanoma, integrative pan-cancer analysis demonstrates that most non-T cell-inflamed tumors are influenced by multiple signaling pathways and that increasing numbers of co-activated pathways leads to more highly non-T cell-inflamed tumors. Validating these analyses, we observe highly consistent inverse relationships between pathway protein levels and the T cell-inflamed gene expression across cancers. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms. Conclusions These results nominate molecular targets and drugs potentially available for further study and potential immediate translation into clinical trials for patients with cancer. |
| first_indexed | 2024-12-21T15:15:58Z |
| format | Article |
| id | doaj.art-e815f477c91d426889e2a3ddaa50db3f |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-21T15:15:58Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-e815f477c91d426889e2a3ddaa50db3f2022-12-21T18:59:10ZengBMCGenome Medicine1756-994X2020-10-0112111910.1186/s13073-020-00787-6Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer typesRiyue Bao0Daniel Stapor1Jason J. Luke2Hillman Cancer Center, UPMCDepartment of Medicine, University of PittsburghHillman Cancer Center, UPMCAbstract Background The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes (i.e., WNT/β-catenin) are known to mediate immunosuppression. Methods We performed an integrated multi-omic analysis of human cancer including 11,607 tumors across multiple databases and patients treated with anti-PD1. After adjusting for TMB, we correlated the T cell-inflamed gene expression signature with somatic mutations, transcriptional programs, and relevant proteome for different immune phenotypes, by tumor type and across cancers. Results Strong correlations were noted between mutations in oncogenes and tumor suppressor genes and non-T cell-inflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c, and genes with unknown functions. Conversely, we observe genes associating with the T cell-inflamed phenotype including VHL and PBRM1. Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion across cancer types (HIF1A and MYC) as well as novel examples in specific tumors such as sonic hedgehog signaling, hormone signaling and transcription factors. Using network analysis, somatic and transcriptomic events were integrated. In contrast to previous reports of individual tumor types such as melanoma, integrative pan-cancer analysis demonstrates that most non-T cell-inflamed tumors are influenced by multiple signaling pathways and that increasing numbers of co-activated pathways leads to more highly non-T cell-inflamed tumors. Validating these analyses, we observe highly consistent inverse relationships between pathway protein levels and the T cell-inflamed gene expression across cancers. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms. Conclusions These results nominate molecular targets and drugs potentially available for further study and potential immediate translation into clinical trials for patients with cancer.http://link.springer.com/article/10.1186/s13073-020-00787-6T cell-inflamedImmune evasionGenomicsTranscriptomicsTCGA |
| spellingShingle | Riyue Bao Daniel Stapor Jason J. Luke Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types Genome Medicine T cell-inflamed Immune evasion Genomics Transcriptomics TCGA |
| title | Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types |
| title_full | Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types |
| title_fullStr | Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types |
| title_full_unstemmed | Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types |
| title_short | Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types |
| title_sort | molecular correlates and therapeutic targets in t cell inflamed versus non t cell inflamed tumors across cancer types |
| topic | T cell-inflamed Immune evasion Genomics Transcriptomics TCGA |
| url | http://link.springer.com/article/10.1186/s13073-020-00787-6 |
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