Erik Henry Knelson, M.D.,Ph.D.
Instructor in Medicine
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
450 Brookline Ave
Boston MA 02215
Available: 11/02/20, Expires: 03/01/21
Clinical trials in thoracic cancers including malignant pleural mesothelioma (MPM) have demonstrated infrequent but promising responses to checkpoint immunotherapy, motivating strategies to promote antitumor immunity. Fundamental barriers include T-cell exclusion and inactivation in poorly inflamed “cold” tumors. Our lab and others have shown that cancer cells suppress cytokine release from viral-sensing pathways to evade immune rejection. Activating the stimulator of interferon genes (STING) pathway potently re-engages innate immunity, and injection of STING agonists causes T cell infiltration and tumor regression in multiple cancer models. While clinical trials of STING agonists have been disappointing, we have discovered therapeutic combinations to enhance antitumor immunity in select patient subsets.
We have profiled STING expression in >300 archival specimens from patients with thoracic malignancies, observing uniformly high STING in MPM. Using fresh surgical specimens, we detect cytokine production from MPM tumor cells treated with STING agonists ex vivo in our organoid system that recapitulates the tumor-immune microenvironment. Tumor cell cytokine release leads to immune activation and cell death in ~50% of MPM tumors. We also observe robust cytokine release in four out of eleven immortalized MPM cell lines treated with STING agonists. It is unclear why certain cell lines and patient specimens respond to STING agonists, while others do not. The proposed question for the HMS scholarly project is what determines STING agonist response in MPM?
Preliminary data in MPM cell lines and patient specimens show uniformly high STING expression and no correlation between histologic subtype of MPM and response to STING agonists. NF2 mutation status and cursory analysis of components of the innate immune cascade were also unrevealing, however the analysis is limited by our inexperience in bioinformatics. The dedicated bioinformatics consultant for the thoracic oncology research group has just taken a position in industry and we need assistance to complete this project for publication in 2021. We are looking for a medical student with previous experience in bioinformatics research to help in assembling a database of gene expression in MPM cell lines (CCLE contains a limited selection), as well as correlative analysis to generate a hypothesis as to why ~50% of patient specimens and cell lines respond to STING agonists. This project has direct clinical relevance, as phase 2 trials for STING agonists in MPM are underway and our lab has the ability to test patient specimens in functional treatment assays. Should the student wish to pursue hypothesis testing after the initial bioinformatics work (which can be conducted remotely during reduced lab availability), the mentor and senior PI are available and interested in supporting wet lab experiments to complete the project. Erik Knelson MD, PhD is a research instructor embedded within the Barbie lab at the Longwood Center, adjacent to the medical school main campus. This opportunity would involve close mentoring by experienced translational scientists seeking to develop novel cancer immunotherapeutics.
The research activities and funding listed below are automatically derived from
NIH ExPORTER and other sources, which might result in incorrect or missing items.
to make corrections and additions.
(KNELSON, ERIK H.)
Apr 1, 2012 - Mar 31, 2014
The Role of Stroma-derived Soluble TbetaRIII in Neuroblastoma
Role: Principal Investigator
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