Cancer Medicine (Apr 2024)

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

  • Jiajun Wang,
  • Sihong Zhang,
  • Ying Wang,
  • Yanjun Zhu,
  • Xianglai Xu,
  • Jianming Guo

DOI
https://doi.org/10.1002/cam4.7113
Journal volume & issue
Vol. 13, no. 7
pp. n/a – n/a

Abstract

Read online

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