Affiliation:
1. The First Affiliated Hospital of Zhengzhou University
2. Huazhong University of Science and Technology
3. Zhengzhou University
4. The First Affiliated Hospital of Xi 'an Jiaotong University
5. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer
6. Chinese Academy of Medical Sciences, Peking Union Medical College
Abstract
AbstractBackground:Tumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC).Methods:Single-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and BEST website.Results:Single-cell analysis revealed that CD8+ T, CD4+ T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4+ T cells in TIME was an independent prognosis factor. After incorporating tumor purity with the ratio of resident to exhausted CD4+ T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlowsubtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylowsubtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis andin vitroexperiments further demonstrated thatSASS6was closely associated with tumor prognosis, proliferation, and migration.Conclusions:The ratio of resident to exhausted CD4+ T cells could serve as a candidate biomarker for evaluating prognosis and potential response to immunotherapy in HCC andSASS6was a novel biomarker and candidate therapeutic target for prognostic assessment of HCC.
Publisher
Research Square Platform LLC