Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types.
Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types.
复制标题
跨癌症类型的T细胞炎症与非T细胞炎症肿瘤的分子相关性和治疗靶点
DOI：
10.1186/s13073-020-00787-6
复制
发表时间：
2020-10-27
期刊：
影响因子：
12.3
通讯作者：
Luke JJ
中科院分区：
文献类型：
--
作者：
Bao R;Stapor D;Luke JJ
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. 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. 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. These results nominate molecular targets and drugs potentially available for further study and potential immediate translation into clinical trials for patients with cancer.
登录
查看更多内容
影响因子：
28.2
作者：
Gstalder C;Liu D;Miao D;Lutterbach B;DeVine AL;Lin C;Shettigar M;Pancholi P;Buchbinder EI;Carter SL;Manos MP;Rojas-Rudilla V;Brennick R;Gjini E;Chen PH;Lako A;Rodig S;Yoon CH;Freeman GJ;Barbie DA;Hodi FS;Miles W;Van Allen EM;Haq R
通讯作者：
Haq R
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.6004/jnccn.2018.7070
发表时间：
2019-03
期刊：
Journal of the National Comprehensive Cancer Network : JNCCN
影响因子：
--
作者：
Johnson DB;Bao R;Ancell KK;Daniels AB;Wallace D;Sosman JA;Luke JJ
通讯作者：
Luke JJ
影响因子：
20.3
作者：
Godfrey, James;Tumuluru, Sravya;Kline, Justin
通讯作者：
Kline, Justin