NOL3 induced feedback loop between RCC cells and TAMs promotes TKI resistance and unfavorable prognosis in renal cancer

Abstract

Abstract TKI resistance of advanced ccRCC patients usually leads to poor prognosis. Interaction between tumor cells and tumor-associated macrophages (TAMs) has been reported to facilitate tumor progression. However, the underlying mechanism remains unclear. This study employed cell functional experiments, IHC, ELISA, and subcutaneous tumor formation models to explore the interaction between ccRCC and TAMs. We found that the expression of NOL3 was upregulated in ccRCC using the online database. The NOL3 over-expressing ccRCC cell lines ACHN and 786-O showed enhanced proliferation and anti-apoptosis ability. In addition, THP1-derived macrophages co-cultured with ccRCC cells exhibited an increased trend towards M2-like polarization. TAMs could stimulate ccRCC to secret more VEGF, which promotes TKI resistance. ccRCC patients from two independent cohorts were screened to investigate the prediction accuracy of NOL3 and the relationship between NOL3 expression and TAMs infiltration. IHC staining quantified by H-score revealed a negative correlation between NOL3 expression and disease progression and a positive correlation with TAMs infiltration. Moreover, NOL3, CD163, and TNM Stage were also found to be the independent risk factors for predicting the outcome of ccRCC patients. Integrating NOL3, TAMs and TNM Stage could predict the prognosis of ccRCC with better accuracy. Overexpressing NOL3 enhanced the infiltration of TAMs and VEGF secretion in mouse tumors, while depletion of macrophages enhanced TKI efficacy. In summary, a positive feedback loop between ccRCC cells and TAMs induced by NOL3 promotes TKI resistance, and targeting NOL3/TAMs might be a potential strategy to alleviate TKI resistance.