Dissecting Mechanisms of Immune Suppression in Tuberous Sclerosis Complex (TSC) by Integrative Single Cell Profiling of Tumor-Microenvironment Interaction
Abstract
Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder that causes the growth of benign tumors in brain, skin, kidney, heart, and other vital organs. The manifestation of TSC in lung (lymphangioleiomyomatosis, LAM) and kidney (angiomyolipomas, AML) can be treated and controlled with inhibitors of the mammalian target of rapamycin (mTOR). However, there is no cure for these diseases, and tumors regrow after the stop of the treatment. The concept that individual’s immune system can be stimulated to scavenge transformed cells is intriguing. However, tumor cells can evolve mechanisms to prevent immune system from recognizing and destroying tumor cells. This mechanism is called “immune suppression.” Groundbreaking advancement of immunotherapies targeting immune suppression in several cancer types in past several years inspired the attempt in TSC immune therapy in our lab. We showed that immune system was suppressed in TSC LAM and AML; targeting immune suppression in preclinical mouse model can reduce tumor size and extend animal survival. This proposal addresses the following areas: (1) Gaining a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency and (2) examining the clinical aspects of TSC, including phenotypic heterogeneity. Like all other tumor types, TSC LAM and AML are pathologically and phenotypically heterogeneous. This project is focused on using cutting-edge single cell technologies to examine tumor heterogeneity and reveal cross-talk among tumor cells, immune system, and other cell types in the tumor ecosystem to facilitate better design of precision immunotherapy for TSC patients with the goal of eliminating these tumors. Despite the exciting advancement in immunotherapy, it does not work for all patients but just benefits a small lucky fraction of patients, which may be attributed to the fact that tumors are not homogenous but consist of different subpopulations, as well as complex tumor ecosystem composed of various cell types that co-evolve with tumor. Precision immunotherapy is emerging as a promising strategy to benefit more patients and reduce the risk of toxicity, which exploits patient-specific, tumor-specific features to develop matched treatments to individual patients to better boost individual immune system against tumor cells. This approach is empowered by the rapidly developing single cell technology that assesses variation of tumors at single cell level to an unprecedented high level of resolution and throughput. My preliminary single cell data revealed multiple mechanisms of immune suppression, implying heterogeneity in tumor cells and other cell types in the ecosystem. My central hypothesis is that heterogeneity in tumor cells and cross-talk of tumor and immune systems contribute to TSC tumor development and initiate multiple immune suppression mechanisms. I will address my hypothesis in two specific aims: (1) Assess heterogeneity in tumor cell population and other cell types in the ecosystem at high-resolution, and identify candidate genes mediating cross-talk between tumor and ecosystem pertinent to immune suppression. (2) Determine whether against-tumor lineages of immune cells are suppressed. My long-term goal is to facilitate development of precision immunotherapies targeting tumor heterogeneity and tumor ecosystems for TSC. The scientific outcomes of this project are (1) identification of genes/pathways in subsets of tumor cells and/or stromal populations affecting immune suppression and (2) delineation of immune clonal suppression mechanisms. The potential translational outcome is development of precision immunotherapy. Briefly, genes/pathways identified in this project can be developed as direct therapeutic targets or can be targets to enhance efficacy of immune therapy in personalized manner. The benefit of this project is that precision TSC immune therapy can be developed based on tumor microenvironment ch
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910152
Entities
People
- Yan Tang
Organizations
- Brigham and Women's Hospital
- United States Army