FHL2 Determines Poor Outcomes and Responsiveness of Immunotherapy Plus Tyrosine Kinase Inhibition in Metastatic Renal Cell Carcinoma
Objectives: Immunotherapy plus a tyrosine kinase inhibitor (IO+TKI) is now the first line therapy for metastatic renal cell carcinoma (mRCC). Nevertheless, IO+TKI treatment's moderate response rate limited the treatment selection for mRCC patients without a useful biomarker in clinical practice.
Methods: Cohorts from our institution and from a clinical study were included (ZS-MRCC and JAVELIN Renal 101). RNA expressions were identified by sequencing. The immune infiltrate and tumor microenvironment were evaluated by flow cytometry and immunohistochemistry.
Results: Participants with high-FHL2 had a lower rate of objective response and a higher non-response rate. Longer PFS was identified in ZS-MRCC and JAVELIN Renal 101 cohorts. In the group with high FHL2, the quantity of tumorinfiltrating lymphocytes was enhanced; however, CD8+ T cells demonstrated an exhaustion phenotype. Incorporating FHL2 expression and TME markers, a machine learning model was constructed using random forest.
Conclusion: There was a strong connection between a high level of FHL2 and immunosuppression, in addition to a
response to IO+TKI treatment. Additionally, there was a connection between T-cell malfunction. The expression of FHL2
was a prognostic factor in mRCC therapy, and the FHL2-based RFscore may serve as a potential biomarker to distinguish an ideal strategy between TKI monotherapy and IO+TKI.
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