Recent studies have shown that cancer cells alter the immune landscape by secreting inflammation-related cytokines or chemokines through a process known as cancer cell-intrinsic inflammation. Cancer cell-intrinsic inflammation facilitates both the initial progression of cancers and cancer metastasis via tumor microenvironment reconstitution, immune surveillance, and premetastatic niche formation. However, in the case of clear cell renal carcinoma (ccRCC), the role of cancer cell-intrinsic inflammation is not fully uncovered. In the present study, we explored the function and regulatory mechanisms of cancer cell-intrinsic inflammation in ccRCC.

First, highly malignant derivatives were obtained through the repetitive exposure of human ccRCC cells into mouse renal microenvironment. Of note, these derivatives elicited cancer cell-intrinsic inflammation in the host mice, which facilitated lung metastasis in neutrophil-dependent manner. Thus, we defined these derivatives as inflammatory ccRCC cells and characterized in the following study.

Next, the regulatory mechanisms for the transcription of genes related to neutrophil dynamics were explored. RNA-sequencing analysis revealed that mRNA-expression levels of four CXC chemokines were up-regulated in all inflammatory ccRCC derivatives. ChIP-sequencing analysis of H3K27ac or bromodomain-containing 4 (BRD4) indicated that super enhancers were recruited at each gene in inflammatory ccRCC derivatives.

Finally, we evaluated the effect of the bromodomain and extra-terminal motif (BET) inhibitor on neutrophil-dependent lung metastasis of inflammatory ccRCC cells. Although the sizes of primary tumors in inflammatory ccRCC derivative-bearing mice were not altered by the treatment of BET inhibitor, those of metastatic lung tumors were significantly decreased.

Overall, our findings revealed a functional role of cancer cell-intrinsic inflammation, which primes neutrophils and drives metastasis of ccRCC cells. The primary tumor microenvironment enriched inflammatory ccRCC cells via epigenetic remodeling. We also showed the utility of inflammation management in suppressing metastasis by utilizing a BET inhibitor.

Citation Format: Shogo Ehata, Jun Nishida, Kosuke Miyakuni, Daizo Koinuma, Kohei Miyazono. BET inhibitor suppresses neutrophil-dependent lung metastasis of inflammatory renal cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4029.