We are investigating the structure and function of RNA-associated cellular machineries involved in immune regulation during the host response to viral infection and cancer, as well as to immunotherapy. Our team has helped to uncover numerous functions of regulatory RNA assemblies in gene silencing, stem cell biology, cancer, immunity, and host–pathogen interactions. In addition, our reports describing genome-wide dynamics of m6A modification of both human and viral RNA during infection with HIV and Zika virus pioneered the new field of epitranscriptomics in virology and immunology. We employ multidisciplinary approaches involving chemistry and biology and, as part of our commitment to translational research, we routinely collaborate with clinicians. Several of the technologies invented and developed by our group have launched biotech companies and have been used to develop small molecule and biologic therapeutics currently in clinical trials.
Here are some examples of three distinct yet interconnected projects currently being pursued in our laboratory:
(1) The recent success of immune checkpoint therapies has transformed our approach to cancer treatment and has galvanized hopes that cures for many types of cancer and, potentially, other diseases are on the horizon. Despite the success of FDA-approved biological therapies targeting CTLA-4 and the PD-L1/PD-1 checkpoints in some cancers, many patients do not respond and the tumors are able to escape therapy. Therefore, we are investigating the fundamental mechanisms that determine whether the host immune system undergoes immune exhaustion leading to tumor evasion or mounts a durable immune response during immunotherapy to various cancers.
(2) One key aspect of the development of AIDS in HIV-infected individuals is exhaustion of the immune system, resulting in an inability to clear infection. However, it is not clear how HIV induces the reprogramming of immune cell populations that culminates in exhaustion. We are currently deciphering the molecular events underlying T cell exhaustion in diverse subsets of HIV-infected individuals.
(3) RNA epigenetics or epitranscriptomics is an emerging field focused on nucleotide modifications in RNA. One such modification is N6-methylation of adenosine (m6A), which plays important roles in regulating RNA metabolism and gene expression. We are interested in understanding how RNA modifications affect the immune system during viral infections and in the development of cancer, primarily glioblastoma.
As a translational research lab, a crucially important aspect of our work is to design and develop novel therapies based on our research findings. The projects outlined above will undoubtedly identify fundamental processes that regulate the immune system in physiological and pathological situations. The knowledge gained and technologies generated during these studies could provide new opportunities to develop novel 'personalized medicines' such as disease-specific rejuvenated T cells, as well as therapies with broader uses such as small molecule and biological therapies and vaccines. Our goal is to develop interventions that enable the patient's immune system to mount durable responses to viral infections and cancer, thereby helping to transform the fields of oncology and virology.
We and our collaborators currently have projects ongoing in glioblastoma, HIV/AIDS, Zika virus, neurodegenerative disease, drug addiction, cancer immunotherapy, and regenerative medicine.