Manipulating Metabolism: An Interview with Dr. Michael St. Paul

Nutrient-limited, hypoxic, and acid­ic – the microenvironment of solid tumors is like a battlefield for effector T cells. What can be done to allow T cells to survive such a hostile climate and ex­ert their antitumor functions? I caught up with a recent alumnus of the de­partment, Dr. Michael St. Paul, to talk about T cell metabolism, cancer immu­notherapy, and his journey as a scientist.

Venturing into the field of metabo­lism Michael’s first exposure to immu­nology research was during his master’s degree at the University of Guelph. His the­sis involved identifying methods to enhance innate immunity against avian influenza vi­rus using chickens as an animal model. After graduating, however, a different field piqued his interest.

“The role of the immune system in cancer treatment was beginning to be appreciat­ed and I was interested in identifying ways in which we could make T cells kill tumor cells better.”

In 2012, Michael joined the Department of Immunology as a PhD student under the su­pervision of Dr. Pamela Ohashi. At first, his project had nothing to do with metabolism. Michael was comparing the antitumor capa­bilities between different CD8+ T cell subsets and demonstrated that IL22-producing cyto­toxic CD8+ T cells (Tc22) were very effective at controlling murine tumor growth.

“We were seeing hints there were metabol­ic differences in [Tc22 cells], and further investigation led us to uncover some inter­esting metabolic findings.”

Those findings were published a few months ago in Cell Metabolism. Compared to other CD8+ T cell subsets, Tc22 cells have enhanced oxidative phosphorylation (OXPHOS), an important pathway in the mitochondria that generates ATP. This was attributed to greater pantothenate/coenzyme A metabolism, which are precursor substrates of the Krebs cycle.

“The most exciting aspect is that metabolic pathways can have profound implications on T cells, and by flipping various meta­bolic switches it is possible to drastically alter T cell phenotype and function.”

For example, enhancing OXPHOS in T cells increases persistence and effector func­tions. When asked about the potential clinical implications of T cell metabolism research, Michael believes the focus will be on adop­tive cell therapy products. This immunother­apy involves expanding tumor-reactive T cells in vitro, then infusing them back into cancer patients. There’s an opportunity during the expansion process to add small molecule in­hibitors, cytokines, costimulatory molecules, or even genetically modify the T cells to boost their metabolic function. Moreover, Michael believes there’s another method that could prove useful.

“Several groups, including ours, have found certain metabolites [like pantoth­enate] to be enriched in the pre-treatment blood of patients who would respond to immunotherapy. So, I think another trans­lational aspect would be to increase the lev­els of metabolites in patients prior to im­munotherapy to see if this could increase response.”

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Lessons learned

Michael successfully defended his thesis during the height of the pandemic in 2020. I asked Michael to reflect on the high­lights of his PhD experience.

“My biggest takeaway was honing my ability to ask a good scientific question. Dr. Pam Ohashi was amazing and encouraged us to ask our own research questions. Half of the time, the questions I thought of ended up not being very good but going through that process myself and learning from those experiences was really beneficial and helped me to become a better scientific researcher.”

Michael’s PhD journey also demonstrates the value of col­laboration. He worked closely with many fellow lab members and external researchers, but none closer than Dr. Sam Saibil. Sam is an alumnus from the Ohashi Lab and is currently a clinician-scientist appointed at the Department of Immunol­ogy. The pair were often seen in deep intellectual conversa­tions, whether it was at the lab bench or over a cup of coffee.

“Sam is incredibly knowledgeable in the field of metabo­lism, immunology, and cell therapy. So by bouncing ideas off each other and discussing the latest papers we were able to come up with some pretty cool ideas together; some of which have led to some unexpected findings.”

Michael and Sam gave crucial input to each other’s proj­ects, resulting in multiple coauthored papers and a lifelong friendship.

To wrap up, I asked Michael if studying metabolism made him more conscientious about his own lifestyle choices.

“Not really. Ramen still makes up 50% of my diet. “

Touché, Michael.

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A new chapter

Michael is now a Post-Doctoral Fellow in Dr. Tak Mak’s lab at Princess Margaret Hospital. His research has shifted away from metabolism but he is still interested in improving T cell antitumor functions. Currently, his project involves finding novel tumor antigens and exploring how tumors evade T cells using cancer patient specimens. For now, Michael is open to working in academia or industry. Regardless of the path he chooses, he intends to stay in the field of cancer immunology and immunotherapy.

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References

1.Paul, M. S., Saibil, S. D., Lien, S. L., Han, S., Sayad, A., Mulder, D., … & Ohashi, P. S. (2020). IL6 induces an IL22+ CD8+ T cell subset with potent antitumor function. Cancer immunology research.

2.Paul, M. S., Saibil, S. D., Han, S., Israni-Winger, K., Lien, S. C., Laister, R. C., … & Ohashi, P. S. (2021). Coenzyme A fuels T cell anti-tumor immunity. Cell metabolism, 33(12), 2415-2427