Long Noncoding RNA Advocates Immune Resistant Microenvironment

项目总结

Project Summary Historically, the majority of relevant research has only interrogated classical pathways in breast cancer cells and has had little success in developing clinical drugs against triple-negative breast cancer (TNBC). Immunotherapy, including PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but the majority of TNBC 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 immunosuppression that develops during TNBC progression. We demonstrated that tumor-resident Schwann cells (refered as TASc) play important roles in promoting an immunosuppressive microenvironment. Tumor- resident Schwann cells 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 (Trp) to Kynurenine (Kyn). The released Kyn in tumor microenvironment further facilitates the expansion of MDSC (myeloid-derived suppressor cells) and quiescence of effector T cells. Therefore, considering tumor- associated Schwann cell and lncRNAs as therapeutic targets may potentially sensitize TNBC to immunotherapy. The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of lncRNAs in breast cancer so that improved strategies can be developed to reduce TNBC morbidity and mortality. Our central hypothesis is that PVT1 facilitates phosphorylation of TDO2 in tumor-associated Schwann cells to promote triple-negative breast cancer immunoresistance, which could be attenuated in vivo using a targeted therapy. We will address our hypothesis from following aspects. 1) We will demonstrate the mechanisms of tumor-associated Schwann cell-dependent immunosuppression (Aim 1). We will determine the underlying molecular mechanisms of PVT1 in regulating the enzymatic activities of TDO2 (Aim 2). 3) We will ascertain the functional importance of tumor-resident Schwann cells and PVT1 using small molecule inhibitor and small molecular inhibitor-conjugated Pvt1 anti-sense oligonucleotides in combination with immunotherapy (Aim 3). Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating immunosuppression, warrants further characterization of Schwann cell-specific lncRNAs and future applications that hinge on their activity. Our goal is to demonstrate that PVT1, expressed in tumor-associated Schwann cells, may serve as a diagnostic marker that predicts a cancer’s sensitivity to immunotherapy. Thus, a strategy that combines immune checkpoint blockers and lncRNA-based therapeutic strategies has the potential to significantly advance TNBC treatment. In the long run, these research findings will benefit the cancer community by introducing the robust clinical effects of targeting tumor-associated Schwann cells and Schwann cells-expressing lncRNAs as promising therapeutic targets.