[ stratifies prognosis and cold tumor microenvironment across different cancer types: an integrated single cell and bulk RNA sequencing analysis].

OBJECTIVE

Immunotherapy has brought significant clinical benefits to a subset of patients, but has thus far been disappointing in the treatment of immunologically "cold" tumors. Existing biomarkers that can precisely identify these populations are insufficient. In this context, a potential cold tumor microenvironment (TME) marker was investigated to reveal its impact on TME and patients' response to immunotherapy across pan-cancer.

METHODS

The expression levels and mutational landscape of in pan-cancer were investigated. Kaplan-Meier and univariate Cox regression analyses were applied to analyze the prognostic significance of . Pathways affected by were investigated by gene set enrichment and variation analysis. The relationship between expression and immune infiltration was examined using the TIMER2 and R packages. Single-cell RNA sequencing (scRNA-seq) data of several cancer types from GSE72056, GSE131907, GSE132465, GSE125449 and PMID32561858 were analyzed to validate the impact of on the TME. The predictive effect of on immunotherapy efficacy was explored in 3 immune checkpoint inhibitors (ICIs)- treated cohorts (PMID32472114, GSE176307, and Riaz2017).

RESULTS

expression was significantly higher in 25 tumor tissues than in normal tissues and was associated with poor prognosis in almost all tumor types. expression exhibited a strong association with several DNA damage repair pathways and was significantly associated with mutation in lung adenocarcinoma ( < 0.0001, OR=2.25). characterized a typical immune desert TME and correlated with impaired expression of chemokines and chemokines receptors. Large-scale scRNA-seq analysis confirmed the immunosuppressive role of and revealed that potentially shapes the cold TME by impeding intercellular interactions. In 3 ICI-treated cohorts, demonstrated predictive value for immunotherapy.

CONCLUSION

This study provides a pan-cancer landscape of the gene by integrated single-cell and bulk DNA sequencing analysis and elucidates its biological function to promote DNA damage repair and construct the immune desert TME, suggesting the potential value of as a novel marker for stratifying patients with poor immunotherapeutic benefits and "cold" TME.