Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

被引:9
|
作者
Lachota, Mieszko [1 ]
Lennikov, Anton [2 ]
Malmberg, Karl-Johan [3 ,4 ]
Zagozdzon, Radoslaw [5 ,6 ]
机构
[1] Med Univ Warsaw, Doctoral Sch, Dept Clin Immunol, PL-02006 Warsaw, Poland
[2] Harvard Med Sch, Dept Ophthalmol, Schepens Eye Res Inst Massachusetts Eye & Ear, Boston, MA 02115 USA
[3] Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, N-0310 Oslo, Norway
[4] Karolinska Inst, Karolinska Univ Hosp, Dept Med Huddinge, Ctr Infect Med, S-14186 Stockholm, Sweden
[5] Med Univ Warsaw, Dept Clin Immunol, PL-02006 Warsaw, Poland
[6] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Regenerat Med, PL-02781 Warsaw, Poland
基金
瑞典研究理事会;
关键词
ANTIGEN EXPRESSION; HLA EXPRESSION; TGF-BETA; T-CELLS; LYMPHOCYTES; ANGIOGENESIS; CANCER; MATRIX-METALLOPROTEINASE-9; CLASSIFICATION; INCREASES;
D O I
10.1155/2021/9920234
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients.
引用
收藏
页数:18
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