Effect of galectin-1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma

Abstract

Background: In renal cell carcinoma (RCC), no clinically available biomarker has been utilized for checkpoint inhibitor immunotherapy (IO) + tyrosine kinase inhibitor (TKI) combinations. Galectin-1 overexpression is found in tumors, with potential immune-regulating roles.

Methods: RNA-sequencing was performed in two cohorts of RCC treated with IO/TKI combination therapy (ZS-MRCC, JAVELIN-101). Immunohistochemistry and flow cytometry were performed to investigate immune cell infiltration and function in the tumor microenvironment of RCC. The RECIST criteria were used to define response and progression-free survival (PFS).

Results: Galectin-1 expression was elevated in RCC with higher stage (p < 0.001) and grade (p < 0.001). Galectin-1 expression was also elevated in non-responders of IO/TKI therapy (p = 0.047). High galectin-1 was related with shorter PFS in both ZS-MRCC cohort (p = 0.036) and JAVELIN-101 cohort (p = 0.005). Multivariate Cox analysis defined galectin-1 as an independent factor for PFS (HR 2.505; 95% CI 1.116-5.622; p = 0.026). In the tumor microenvironment, high galectin-1 was related with decreased GZMB+CD8+ T cells (Speraman's ρ = -0.31, p = 0.05), and increased PD1 + CD8+ T cells (Speraman's ρ = 0.40, p = 0.01). Besides, elevated number of regulatory T cells (p = 0.039) and fibroblasts (p = 0.011) was also found in high galectin-1 tumors. Finally, a random-forest score (RFscore) was built for predicting IO/TKI benefit. IO/TKI therapy showed benefit only in low-RFscore patients (HR 0.489, 95% CI 0.358-0.669, p < 0.001), rather than high-RFscore patients (HR 0.875, 95% CI 0.658-1.163, p = 0.357).

Conclusions: High galectin-1 indicated therapeutic resistance and shorter PFS of IO/TKI therapy. High galectin-1 also indicated CD8+ T cell dysfunction. High galectin-1 could be applied for patient selection of IO/TKI therapy in RCC.

Keywords: T cell exhaustion; galectin‐1; immune checkpoint inhibitor; renal cell carcinoma; tyrosine kinase inhibitor.