Ten new research projects have been selected for the most recent round of funding through the University of Michigan Health System’s Joint Institute partnership with Peking University Health Science Center.
This year’s cohort of new projects represents largest since the Joint Institute was formed eight years ago. The projects, each co-led by a UMMS faculty member and their PUHSC partner, span a number of areas, from exploring the genetic causes of intellectual disabilities to studying whether and how risk complications from diabetes differ between the U.S. and Chinese populations. Congratulations to the following grant recipients!
Identification of Tumoricidal T Cell Receptors from Hepatocellular Carcinoma-infiltrating CD8+ T Lymphocytes
UMMS: Clifford Cho, MD, FACS
PKUHSC: Yuan Hong, MD, PhD
Hepatocellular carcinoma (HCC) is an aggressive malignancy whose poor prognosis is driven in part by a lack of curative treatment options. We previously cloned three novel HCC-specific murine T cell receptor (TCR) genes that can redirect human T cells to effectively eliminate HCC tumor cells, demonstrating the potential to engineer a patient’s autologous T cells to treat HCC. In addition, we have isolated specific CD8+ tumor infiltrating lymphocytes (TILs) from HCC patients and observed their potent antitumor function after in vitro proliferation. In this project, we seek to infuse CD8+ TILs derived from HCC patients into immunodeficient mice harboring autologous HCC, and subsequently clone TCR genes from patient-derived CD8+ T cells with antitumor phenotype. Following validation of their functions, we will determine their targeted tumor antigens through epitope prediction algorithms and unbiased screening using yeast-display libraries. In sum, we will identify novel tumoricidal TCR genes from HCC CD8+ TILs, thereby engineering patient-derived autologous T cells to generate potently tumoricidal TCR-T lymphocytes to treat HCC patients.
Therapeutic Implications of Natural Killer Cell Immune Surveillance in Lung Cancer
UMMS: Venkateshwar Keshamouni, PhD
PKUHSC: Jun Wang, MD, PhD
Lung cancer is the leading cause of cancer mortality worldwide. Use of immune-checkpoint blockers has yielded impressive clinical benefit, but only in a subset of patients. Recent studies demonstrate that the expression of the checkpoint-ligands like PDL-1 on host cells, rather than on cancer cells, determines the efficacy of checkpoint-blockade in mice. A number of host immune cells, including NK cells, express PDL-1 and could dictate the efficacy of checkpoint-inhibitors in humans. A recent phase I/II study combining anti-KIR (an inhibitory NK cell receptor) antibody with anti-PD1 antibody in head & neck cancer showed a dramatic 24% objective response rate over 13.3% with anti-PD1 alone. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process by which epithelial cancer cells acquire migratory and invasive capabilities to metastasize. We demonstrated that a 20-gene EMT-signature is predictive of survival in non-small cell lung cancer (NSCLC) patients. More recently, we showed that EMT-induced expression of a cell-adhesion molecule CADM1 renders cancer cells more susceptible to NK cytotoxicity and inhibits metastasis. This proposal will test whether boosting NK cell functions can control metastasis and whether the EMT signature can be predictive of anti-tumor efficacy of NK cell therapy, as well as response to checkpoint-blockade therapy in NSCLC. The study seeks to provide proof-of-principle for a potential phase I/II study for proposed NK cell-based strategies, along with the support to the potential of EMT-signature and NK cell phenotype in predicting response to checkpoint-blockade and pave the way for subsequent mechanistic studies.
Rapid identification of Pathogens in Ventilator-associated Pneumonia Using Real-time Metagenomics and Real-time PCR
UMMS: Robert Dickson, MD
PKUHSC: Ning Shen, MD
Ventilator-associated pneumonia (VAP) is a tremendous cause of morbidity, mortality, and healthcare expense in China and the United States. Clinical identification of respiratory pathogens still relies on the culture-based techniques used by Pasteur in the 1880s. Delayed identification of pathogens in pneumonia results in increased morbidity and mortality, and indiscriminate use of broad empiric antibiotics impedes antimicrobial stewardship. The long-term objective of this proposal is to accelerate the identification and quantification of pathogens in VAP using novel, real-time molecular technologies. We will develop a protocol and pipeline that will rapidly identify respiratory pathogens in four hours via real-time metagenomics. In addition, we will develop a protocol and determine reference ranges that will rapidly quantify respiratory pathogens in two hours using a novel ultrasensitive PCR platform.
Integrative and Trans-ethnic Cutaneous T-cell Lymphoma (CTCL) Study to Reveal Clinical and Molecular Determinants for Disease Prognosis
UMMS: Lam Tsoi, PhD & Trilokraj Tejasvi, MBBS, MD
PKUHSC: Yang Wang, MD
Cutaneous T-cell lymphoma (CTCL) is a major form of the primary cutaneous lymphomas and affects all populations in the world including the American and Chinese. CTCL symptoms range from mild itchy red patches to large, painful, disfiguring, cerated nodules, and patients with the advanced stages of CTCL only have up to a 50% three-year survival rate. CTCL patients respond differently to current available treatments, and the subtypes (e.g., Sézary syndrome) vary greatly in their relapse-rate and prognosis. While we and others have conducted population-specific genetic, epidemiological, and/or molecular studies, there has not been any cross-ethnic study to systematically evaluate the shared/unique risk factors associated with prognosis cross populations. With CTCL being an uncommon cancer with limited armamentarium in management, it is imminent to identify robust prognosis biomarkers. This project will set forth the first collaboration between the UMHS Department of Dermatology and the PUHSC Department of Dermatology, as well as Venereology from the Peking University First Hospital, drawing on the unique resources and the expertise of the investigators from the two institutions.
β-adrenergic Receptor Activation in Cardiac Injury and Atherosclerotic Plaque Stability: Role of NPDPH Oxidase 4 (NOX4)
UMMS: Marschall Runge, MD, PhD
PKUHSC: Youyi Zhang, MD, PhD
Cardiovascular disease (CVD) is the leading cause of death worldwide, representing 31% of all deaths. Emerging evidence suggests that stress in adulthood acts as a disease trigger in individuals with high atherosclerotic burden and is a determinant of prognosis and clinical outcomes. Increases in cardiovascular events were reported immediately after traumatic events such as natural disasters, war, and terrorist attacks of 9-11. Although the link between various stressors and disease end points is obvious, much less is known how the pathophysiological mechanisms through which stress responses transform into changes that initiate the development and progression of CVD. Another challenge is addressing the stressors by intervention, because such events are stochastic and therefore difficult to predict. We propose to elucidate the molecular signaling pathways which regulate the transformation of stress responses into cardiovascular events in people with atherosclerotic burden using mouse models of oxidative stress available in the Runge laboratory. These studies will establish the role of NOX4 NADPH oxidase in cardiovascular events in the backdrop of high atherosclerotic burden and potentially identify strategies that work in concert with standard of care treatment for the prevention of cardiovascular events under stress conditions.
Targeting Tumor Neoantigen-specific Tumor Infiltrating Lymphocytes in Non-small Cell Lung Cancer
UMMS: Andrew Chang, MD
PKU Shenzhen Hospital: Jixian Liu, MD
Tumor infiltrating lymphocytes (TILs) comprise a subset of white blood cells isolated from the tumor and surrounding parenchyma that are thought to mediate tumor-specific immune responses. Autologous TIL cultures, isolated from resected tumor tissue, expanded ex vivo and subsequently reinfused into the preconditioned donor patient, have been shown to elicit durable response rates with some instances of long-term survival. In contrast, another subset of TILs appears to attenuate clinical response. We hypothesize that TILs which recognize tumor-specific neoantigens originate from somatic mutations and are more effective in eliciting a clinically significant response. As proof of concept, it has been shown that TILs harvested from resected metastatic lung tumors from a subject with metastatic colorectal carcinoma recognized neoantigens generated by the mutant KRAS-G12D. Re-infusion of expanded TILs led to a significant antitumor response in this subject. The aim of our study is to utilize high throughput sequencing and tetramer flow cytometry to identify tumor-specific neoantigens derived from patients with non-small cell lung carcinoma, both adenocarcinomas and squamous cell carcinomas, as a prelude to the treatment of NSCLC patients with autologous T cells.
Understanding the Heterogeneity in the Risk of Diabetes Complications in China and the US
UMMS: Rodica Pop-Busui, PhD
PKUHSC: Lixia Zhang, MD, MPH
The global trend towards obesity, physical inactivity and energy-dense diets has led to a rapid rise in the prevalence of diabetes. It is estimated that 415 million people live with diabetes, with a projected increase to 642 million by 2040. Practical and cost-effective interventions at national levels are essential to attenuate the global burden of diabetes. Current evidence have shown that glucose control designed to achieve near-normal glycemia may reduce the risk of chronic complications in patients with type 1 diabetes (T1D) and some patients with type 2 diabetes (T2D). However, a critical knowledge gap remains in understanding what persons with diabetes do or do not develop complications, independently of glucose control, and whether there are populations and regions-specific differences in this risk. We hypothesize that populations from different ethnic origin/regions express diverse specific phenotypes of diabetes and its complications and hope to identify mechanism-based therapies for the treatment of diabetes complications so treatment can be individualized and targeted appropriately.
Inflammatory Mediators of Cardiac and Other End Organ Dysfunction During Venoarterial Extra-corporeal Membrane Oxygenation
UMMS: Paul Tang, MD, PhD
PKUHSC: Feng Wan, MD
Cardiovascular disease is the leading cause of death in the world. The use of extracorporeal membrane oxygenation (ECMO) for the treatment of cardiopulmonary collapse has risen exponentially. Data show that 86,287 cases of extracorporeal membrane oxygenation were performed in 2017. Of these 10,982 cases were performed for cardiogenic shock. Thus, the complications and morbidities of ECMO has an enormous impact on resource utilization as well as patient outcomes. A major complication that impairs patient survival is the impairment of end organ function associated with ECMO-induced inflammation. Furthermore, this inflammation can impact myocardial recovery and predict right heart failure after bridge of ECMO to a left ventricular assist device (LVAD). Right ventricular failure after LVAD implant is also a predictor of prolonged hospitalization as well as increased patient morbidity and mortality. Our objective is to determine the association of ECMO mediated inflammation with end organ dysfunction including impairment of myocardial function. Distinct from previous studies, this investigation will focus on patients undergoing venoarterial ECMO for cardiogenic shock either in the setting of acute cardiac decompensation or failure to wean from cardiopulmonary bypass after cardiac surgery.
Identification and Establishment of Novel Pathogenic Genes Involved in Intellectual Disability/ Developmental Delay with Hypomyelinating Leukodystrophy in China
UMMS: Margit Burmeister, PhD
PKUHSC: Jimgmin Wang, PhD
Intellectual disability/development delay (ID/DD) is a common group of neurodevelopmental disorders characterized by substantial limitations in both intellectual functioning and adaptive behavior, starting before the age of 18 years with a prevalence of 1%~3%. Genetics is known to have an important role in etiology of ID/DD. Discerning the precise genetic causes for specific ID/DD patients will inform prognosis, management and therapy, enables access to disorder-specific support groups, and facilitates family planning. Specific knowledge of the genetic basis of disease may in some cases also lead to direct therapeutic interventions. Trio-based whole exome sequencing (WES) has become the best option to identify genetic causes of ID/DD. Although rare variants in more of >700 different genes have now been shown to be associated with ID/DD, many disease-causing genes still remain to be discovered. Building on prior collaborations, we aim to identify and further study genetic causes of ID/DD&HLD patients. Establishing neuronal cell lines for promising candidate gene variants will provide a cellar platform for pathogenesis studies and in-vitro drug screens.
Systematic Investigation of the Microbiome-host Interactions in H. pylori-associated Gastric Cancer Patients
UMMS: Yongqun He, PhD
PKUHSC: Jianmin Wu
Gastric cancer is the fifth most prevalent malignancy and the third leading cause of cancer death worldwide. Almost a half of new cases of gastric cancer occurred in China, where it is the second leading cause of cancer death. The strongest risk factor for gastric cancer is chronic Helicobacter pylori infection. People with H. pylori infection have a roughly six-fold greater risk of developing gastric cancer than uninfected people. However, not all people infected with H. pylori will develop gastric cancer, suggesting more factors and mechanisms involved in gastric carcinogenesis. We hypothesize that complex interactions between host genetic susceptible factors, H. pylori, and other gut microbes influence the host molecular and cellular activities, leading to the development of gastric cancer. Our study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis, with ex vivo verification using organoid models. This systematic study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis and provide proof-of-concept ex vivo experimental verification using organoid models, leading to further understanding of gastric carcinogenesis.