Presentation Authors: Huyang Xie*, Nantong, China, People's Republic of, Junyu Zhang, Yongqiang Huang, Shanghai, China, People's Republic of, Yeqing Huang, Qianwei Xing, Nantong, China, People's Republic of, Jiejie Xu, Dingwei Ye, Shanghai, China, People's Republic of
Introduction: Neutrophils are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironment. However, the nature, regulation, function and clinical relevance of neutrophils in human renal cancer are presently unknown. We investigated clinical relevance, phenotypes, and functional features of renal cancerâ€“infiltrating neutrophils and their crosstalk with CD8+ T cells.
Methods: CD66b+ and CD8+ cell infiltration was analyzed by IHC on a tissue microarray including 237 evaluable renal cancer samples. Flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from patients. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays.
Results: Patients with renal cancer showed a significantly higher neutrophil infiltration in tumors. These tumor infiltrating neutrophils showed an activated CD54+ phenotype and expressed high level galectin-9 (Gal-9). Neutrophils activated by tumors prolonged their lifespan and strongly expressed Gal-9 proteins with similar phenotype to their status in renal cancer, and significant correlations were found between the levels of Gal-9 and CD54 on tumor-infiltrating neutrophils. Moreover, these Gal-9+ neutrophils in tumors were associated with disease progression and reduced patient survival. Tumor-derived TGF-Î² activated neutrophils and induced neutrophil Gal-9 expression. The activated Gal-9+ neutrophils effectively suppressed normal T-cell immunity in vitro and contributed to the growth and progression of human renal cancer in vivo; the effect could be reversed by blocking Gal-9 or Tim-3 on CD8+ T cells.
Conclusions: Our results illuminate a novel mechanism of Gal-9 expression on tumor-activated neutrophils in renal cancer, and also provide functional evidence for these novel TGF-Î²-Gal-9-Tim-3 pathways to prevent, and to treat this immune tolerance feature of renal cancer.