Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

The tumor microenvironment impacts tumor progression and individual cells, including CD4+ T cells, have been detected in bladder cancer (BCa) tissues. The detailed mechanism how these T cells were recruited to the BCa tumor and their impact on BCa progression, however, remains unclear. Using a human clinical BCa sample survey and in vitro co-culture system, we found that BCa has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in BCa included increased BCa metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL-1 which increases the recruitment of T cells to BCa and enhances the BCa androgen receptor (AR) signaling that results in increased BCa cell invasion via up-regulation of HIF-1α/VEGFα expression. Interruption of the IL-1→AR→HIF-1α→VEGFα signals with inhibitors of HIF-1α or VEGFα partially reversed the enhanced-BCa cell invasion. Finally, in vivo mouse models of xenografted BCa T24 cells with CD4+ T cells confirmed in vitro co-culture studies and concluded that infiltrating CD4+ T cells can promote BCa metastasis via modulation of the IL-1→AR→HIF-1α→VEGFα signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress BCa metastasis.