Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer

In patients with bladder cancer, programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors have been shown to be effective in around twenty percent of patients, and there is evidence indicating that the level of immune infiltration and immune suppression within the tumor microenvironment correlates with response to these treatments. We have previously shown that there are intrinsic subtypes of bladder cancer, with the basal subtype characterized by high levels of immune infiltration, and the luminal subtype characterized by immune exclusion. Here we show that treatment with current standard of care chemotherapeutic agents has a subtype specific effect on the tumor microenvironment. Cisplatin-based chemotherapeutic treatment of luminal tumors induces a mesenchymal phenotype, immune infiltration, and a transition to a more basal-like tumor, while not altering these characteristics of the tumor microenvironment in basal tumors. Two of the most widely used standard of care chemotherapeutic regiments are Cisplatin-Gemcitabine (GemCis) and Methotrexate-Vinblastine-Doxorubicin-Cisplatin (MVAC), and we show that MVAC treatment induces significant immune infiltration within the luminal subtype while GemCis treatment does not, indicating there are treatment specific effects on the immune microenvironment. Furthermore, using mouse models of bladder cancer previously developed by our lab that accurately reflect the basal and luminal subtypes of bladder cancer, treatment with a representative chemotherapeutic regimen induced immune infiltration in the luminal mouse model while not affecting the tumor immune microenvironment in the basal mouse model. These results indicate chemotherapeutic regimens have subtype specific effects on the tumor microenvironment which could potentially be used to increase the efficacy of immune checkpoint inhibitors. Citation Format: Jordan Kardos, Lisa Bixby, Andrew Truong, Bhavani Krishnan, Kyle Stewart, Benjamin Vincent, William Kim. Effects of subtype specific chemotherapeutic immunomodulation in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2749.