Invigorating Immunotherapy with Epigenetic Modulation

I remember the most fascinating moment was when our compound worked successfully in the in vivo mouse tumor model. We successfully validated different aspects of EnPGC-1 functioning on primary murine immune CD8 T cells in various in vitro systems, however, we were not sure whether it would work in the in vivo system since many factors affect in vivo functions such as target specificity, retention time, and cross-reaction, etc. When we treated colon carcinoma-bearing mice with PD-1 blockade in combination with EnPGC-1, to our surprise, we found the combination therapy had significantly boosted the immune response and caused more tumor regression compared to PD-1 blockade alone. EnPGC-1 in combination with PD-1 blockade also improved the survival of the host. It was the most gratifying moment for me to know that my compound worked successfully in vivo. Showing that this designer molecule could have clinical benefits and the potential to be used to treat cancer patients was a major achievement for us. I can say that this moment deserves to be proclaimed as the “I made it” moment.

During this project, we wanted to have concrete evidence of the biological feasibility and effectiveness of EnPGC-1 functioning. It was difficult to decide which assay would show a direct correlation of measurable biological phenomenon to EnPGC-1 mediated PGC-1α/β upregulation. Because PGC-1 upregulation has a positive impact on mitochondrial biogenesis and respiration, we decided measuring mitochondrial respiration could give us the best observation of PGC-1 enhancement in immune cells. Since oxygen is the terminal electron acceptor in the electron transport system, the consumption of oxygen in the cells from the media could give a direct correlation. We measured the mitochondrial respiration by assessing the oxygen consumption using a Seahorse Analyzer, an instrument which measures the consumption of oxygen and the pH change in the culture plate. The measurement of mitochondrial respiration directly supported our hypothesis that EnPGC-1 enhances mitochondrial respiration by increasing PGC-1α/β.

In this research, we have shown for the first time the use of an epigenetic modulator to enhance cancer immunotherapy efficacy. Yes, I think this work is a turning point in my overall research direction. I believe this work is opening a new avenue for the development of an artificial biomimetic epigenetic modulator to effectively control the various immune response-associated genes to improve cancer immunotherapeutic efficacy. The knowledge gained during this research will be helpful in future research and this platform can be useful in designing epigenetic regulators for any gene that curbs disease, for example, treating type 2 diabetes, enhancing fatty acid oxidation associated key genes to treat hyperlipidemia, and enhancing TNF-α in killer cells to control cancer cells.

iCeMS is one of the world-renowned research institutes. The high standard of research by scientists from various disciplines at iCeMS has set an example for the world. The novel high quality research there always inspired me and boosted my passion for conducting better scientific research. Several scientific meetings and interactive seminars hosted by iCeMS motivated and encouraged me to acquire the latest ideas for research. Technically advanced instruments at iCeMS helped me to design and perform my experiments in a feasible and easy way. The collaborative work environment involving various disciplines motivates and provides a common platform for students to learn from each other. I gained a lot of knowledge about immunotherapy approaches during my research. From this winter, I have my research as a postdoc at the University of Pittsburgh, Pittsburgh, USA.

*All the information on this page, including the researcher’s affiliation, is current at the time of the interview.