of Work Malignant gliomas confer a dismal prognosis and have an inherent tendency to recur despite the most aggressive of therapies. Recently, significant progress has been made in both understanding the genetic foundation of these tumors as well as how to harness the power of the immune system to target these most devastating tumors. While there has been substantial evidence in support of using T cells to treat established tumors in mice and humans, the translational value of these treatments has been limited by the simplicity of glioma models used for their development: mostly relying on transplanted tumors that do not recapitulate the immune microenvironment present in human gliomas. To this end, this proposal seeks to develop a spontaneous and genetically faithful mouse glioma model by combining the initial IDH1R132H driver mutation with other most common mutations. These models will maintain the integrity of the immune microenvironment of the brain and best recapitulating human glioma. With these models, we will also assess the interplay between glioma development and the immune response as dictated by different genetic mutations.
Our second aim i s to identify IDH1R132H reactive T cell antigen receptors (TCRs).
We aim to improve the current technology which employs single cell RNAseq to clone both the TCR? and TCR? chains. We will optimize the current cloning procedures to dramatically reduce the reagent expense and labor cost, which is essential for its clinical application.
This aim will be extended into a translational direction, aim 3, through genetic engineering of T cells to redirect their antigen specificity against IDH1R132H.
This aim i s essentially a proof-of-principle study for TCR-T adoptive transfer immunotherapy in our immune-competent mouse glioma models. Combined, novel animal models and technologies developed in this study will help elucidate the complexities underlying glioma genetics and how these commonly mutated genes contribute to glioma development, progression, and glioma-specific immune suppression mechanisms. In addition, this will also facilitate the development and implementation a novel strategy for glioma immunotherapy.
This project has two aims: 1) we will develop novel animal models to address the complexities underlying glioma genetics and how common genetic mutations contribute to glioma-specific immune suppression; 2) we will develop a reliable and cost-effective single cell RNAseq platform to analyze and clone T cell receptors against IDH1R132H, an initial driver mutation for glioma tumorigenesis. This is highly relevant to the Beau Biden Cancer Moonshot, which is intended to accelerate cancer research: malignant gliomas confer a dismal prognosis and have an inherent tendency to recur despite the most aggressive of therapies. Expected results from this project not only establish the foundation for future glioma tumorigenesis study, but also provide new strategies for glioma immunotherapy.
| Zhao, Lintao; He, Ran; Long, Haixia et al. (2018) Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med 24:1536-1544 |
