Molecular Mechanisms of Bladder Cancer Immunometabolism

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Project Summary Historically, the majority of relevant research has only interrogated classical pathways in bladder cancer cells and has had little success in developing clinical drugs against bladder cancer (BC). Immunotherapy, including PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but the majority of BC cases are regarded as resistant or immune-quiescent tumors and are unresponsive to single checkpoint treatments. These challenges demand definition of the molecular mechanisms underlying the immuno- suppression that develops during BC progression. We demonstrated that tumor-resident Schwann cells (referred as TASc) play important roles in promoting an immunosuppressive microenvironment. TAScs express one lncRNA that modulates RAF1-mediated phosphorylation of TDO2 (Tryptophan 2,3-Dioxygenase), thereby facilitating the enzymatic activities of TDO2 and catalysis of Tryptophan to Kynurenine. The released Kynurenine in tumor microenvironment further facilitates the expansion of MDSC (myeloid-derived suppressor cells) and quiescence of effector T cells. Therefore, considering TAScs and lncRNAs as therapeutic targets may potentially sensitize BC to immunotherapy. The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of lncRNAs in BC so that improved strategies can be developed to reduce BC immune resistance. Our central hypothesis is that PVT1 facilitates phosphorylation of TDO2 in TAScs to promote BC immunoresistance, which could be attenuated in vivo using a targeted therapy. We will address our hypothesis from following aspects. 1) We will demonstrate the prognostic value of TAScs in BC and determine the functional importance of TASc expressing lncRNA in BC tumorigenesis (Aim 1). We will determine the underlying molecular mechanisms of lncRNA in regulating the enzymatic activities of TDO2 and the IL-6 induced, RAF1-mediated phosphorylation of TDO2 (Aim 2). 3) We will ascertain the functional importance of TAScs using small molecule inhibitor and small molecule inhibitor-conjugated anti-sense oligonucleotides, anti-IL-6 neutralization antibody, or kynurenine aminotransferase inhibitor in combination with immunotherapy in inhibiting BC immune resistance and metastasis (Aim 3). Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating immunosuppression, warrants further characterization of TASc-specific lncRNAs and future applications that hinge on their activity. Our goal is to demonstrate the underlying mechanisms of BC immune resistance from lncRNA and metabolite points of view. Thus, a strategy that combines immune checkpoint inhibitors and lncRNA- based therapeutic strategies has the potential to significantly advance BC treatment. In the long run, these research findings will benefit the cancer community by introducing the robust clinical effects of targeting TAScs and TASc-expressing lncRNAs as promising therapeutic targets.