Soluble TIM-3, likely produced by myeloid cells, predicts resistance to immune checkpoint inhibitors in metastatic clear cell renal cell carcinoma
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Background and objectives
Immunotherapies targeting PD-1 and CTLA-4 are key components of the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, they have distinct safety profiles and resistance to treatment can occur. We assess soluble TIM-3 (sTIM-3) in the plasma of mccRCC patients as a potential theranostic biomarker, as well as its source and biological significance.
Methods
We analyzed the association of sTIM-3 with overall survival (OS), tumor response, and common clinical and biological factors across two mccRCC cohorts treated with anti-PD-1 (n = 27), anti- PD-1 or anti-PD-1 + anti-CTLA-4 (n = 124). The origin and role of sTIM-3 are studied on tumor and blood samples, using multiplex immunohistochemistry and flow cytometry as well as a syngeneic tumor model with antitumor vaccination. We also reanalyzed publicly available single-cell transcriptomic (scRNAseq) data and mass cytometry data.
Key findings and limitations
sTIM-3 is elevated in the plasma of patients with mccRCC and shows distinct associations with survival on anti-PD-1 vs anti-PD-1 + anti-CTLA-4. sTIM-3 is independent from other clinical and biological factors. Myeloid immune cells appear as the prominent source of sTIM-3, which may indicate their dysfunctional role in the antitumor immune response. Future investigations are warranted in patients treated with anti-PD-1 + antiangiogenic therapies. Further functional studies are needed to confirm its theranostic value and clarify its role in the immune response.
Conclusions and clinical implications
sTIM-3 appears to be a promising biomarker for optimizing treatment strategies in ccRCC as well as a potential therapeutic target.
