Cross talk between tumor stemness and microenvironment for prognosis and immunotherapy of uveal melanoma.

purposeTumor stem cells have emerged as a crucial focus of investigation and a therapeutic target in the context of cancer metastasis and drug resistance. They represent a promising novel approach to address the treatment of uveal melanoma (UVM).

methodsAccording to the one-class logistic regression (OCLR) approach, we first estimated two stemness indices (mDNAsi and mRNAsi) in a cohort of UVM (n = 80). The prognostic value of stemness indices among four subtypes of UVM (subtype A-D) was investigated. Moreover, univariate Cox regression and Lasso-penalized algorithms were conducted to identify a stemness-associated signature and verify in several independent cohorts. Besides, UVM patients classified into subgroups based on the stemness-associated signature. The differences in clinical outcomes, tumor microenvironment, and probability of immunotherapeutic response were investigated further.

resultsWe observed that mDNAsi was significantly linked with overall survival (OS) time of UVM, but no association was discovered between mRNAsi and OS. Stratification analysis indicated that the prognostic value of mDNAsi was only limited in subtype D of UVM. Besides, we established and verified a prognostic stemness-associated gene signature which can classify UVM patients into subgroups with distinct clinical outcomes, tumor mutation, immune microenvironment, and molecular pathways. The high risk of UVM is more sensitive to immunotherapy. Finally, a well-performed nomogram was constructed to predict the mortality of UVM patients.

conclusionsThis study offers a comprehensive examination of UVM stemness characteristics. We discovered mDNAsi-associated signatures improved the prediction capacity of individualized UVM prognosis and indicated prospective targets for stemness-regulated immunotherapy. Analysis of the interaction between stemness and tumor microenvironment may shed light on combinational treatment that targets both stem cell and the tumor microenvironment.