CPF1-Guided In Vivo Genomewide Screen for Discovery of Immunotherapy in Pancreatic Cancer
Abstract
Pancreatic cancer is among the deadliest of human cancers and has recently surpassed breast cancer to become the third-leading cause of cancer-related death in the United States. This is due to the fact that pancreatic cancer is usually diagnosed too late and no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Recently, the application of immunotherapy, a type of cancer treatment that manipulates human immune system to fight cancer, has generated much excitement in treating several tumor entities. The clinical success of immunotherapy suggests that it has become a central part of cancer therapy for many types of tumors, such as skin and lung cancers. However, these immune therapies have not worked against pancreatic cancer. This disappointing result has been largely caused by the tumors preventing the immune system activity. It has been appreciated that crosstalk between pancreatic ductal adenocarcinoma (PDAC) cells and immune cells in the tumor progression can not only result in, or be influenced by different tumor features, but it can also lead to diverse ways to escape the immune system. Preclinical data have supported that PDAC cells can employ multiple means to avoid recognition by immune cells, allowing them to escape from immune control and continue cancer progression. Actually, among patients who do respond to immunotherapy, many responses do not last. All the evidences suggest that it is critical to target the key genes that prevent this resistance. Applicability: Genome-wide identification and characterization of key immunomodulatory genes and pathways in in vivo setting remains a critical bottleneck in the expansion of the immunotherapeutic armamentarium. To address this unmet need, we have recently developed a new screening methodology which will identify genetic underpinnings at genome-scale in vitro. Furthermore, we optimize the screen system for in vivo screen manipulation in PDAC immunocompetent model. The studies proposed here will take strategic advantage of this novel unbiased genome-scale screen platform to accomplish the AsCpf1-based whole genome screen of immunotherapeutic targets. We will then validate the identified genes using a pooled secondary screen as well as individual gene editing. Finally, we will characterize the phenotype of selected candidate genes in PDAC system. If successfully accomplished, this proposed research will provide the first genome-scale view of PDAC immunomodulation and will substantially expand our knowledge of how PDAC cells influence immunosuppressive environment. Insights gleaned from these studies will help improve the efficacy and safety of cancer immunotherapy, and will facilitate the development of new therapeutics for immune disorders caused by cancer cell intrinsic molecular underpinnings. The final outcome of our proposed research is aiming to help patients with pancreatic cancer towards more effective immunotherapy. As a result, this study should have an immediate translational impact on the development of novel immunotherapeutic targets or combinatory strategies to treat pancreatic cancer. Since immunotherapy resistance has also commonly happened in other tumors, including both immunosensitive and non-immunosensitive tumor types, our proposed studies will go beyond pancreatic cancer by providing rational to overcome the resistance to immunotherapies and improving patient survival. Military relevance: Pancreatic cancer cases linked to exposure to cigarette smoking and diabetes have been shown to disproportionately affect active Service members, Veterans and their dependents. Despite the huge medical expense on Veterans and other military beneficiaries with pancreatic cancer, the clinic outcomes remain disappointing due to the ineffective response to current therapies. Our proposed study to systematically explore the molecular determinants of tumor maintenance and to identify specific therapeutic targets
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010598
Entities
People
- Wantong Yao
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army