Mayo Clinic Graduate School of Biomedical Sciences Ph.D. graduate Joanina Gicobi recently completed her thesis on finding ways to improve cancer treatment by tapping into the body’s natural ability to fight tumors. Under the guidance of Dr. Haidong Dong, Gicobi and a team of Mayo Clinic researchers made a breakthrough in understanding CD8+ T cells, the body’s cancer-killing immune cells.
The team’s research, published in Science Advances, reveals the existence of a new type of CD8+ T cell that can withstand the toxicity of chemotherapy and radiation therapy. These resilient T cells remain functional even after treatment, suggesting that they could be used to target cancer using the immune system. Additionally, the team identified a potential strategy to enhance the cancer-killing abilities of these robust cells.
One aspect that has puzzled researchers is the persistence of CD8+ T cells, especially in patients who have exhausted all other treatment options. Even after multiple rounds of therapy that not only eliminate cancer cells but also immune cells, some patients still have circulating cancer-fighting CD8+ T cells in their blood. These cells, although weakened, are capable of triggering an immune response.
However, until now, the specific nature of these CD8+ T cells remained unknown. Dr. Dong explains that the lab encountered several obstacles while trying to characterize the cells. Despite hitting dead ends, the team stayed persistent in their pursuit of answers.
To better understand these rebounding T cells, Gicobi conducted research to identify their unique molecular markers. Using RNA sequencing, she discovered that these resilient T cells had slightly different gene expressions compared to typical CD8+ T cells. One gene caught her attention, as it was related to the cells’ metabolic pathway. This finding led Gicobi to investigate the metabolic aspects of these cells further.
The team discovered that the resilient T cells exhibited higher levels of an enzyme called malic enzyme 1 (ME1). This enzyme plays a crucial role in the reduction of reactive oxygen species, which are toxic byproducts of cellular metabolism that affect immune cell function. The increased expression of ME1 in resilient T cells solidified their distinction as a unique subgroup of CD8+ T cells.
Dr. Gicobi then speculated that manipulating ME1 could enhance the function and energy of immune cells, increasing their response to tumors. Through laboratory experiments, she engineered the resilient T cells to overproduce ME1. The results showed that the increased levels of ME1 rejuvenated the cells and made them more effective at killing tumor cells. Importantly, Gicobi noted that the enhanced cancer-killing capacity occurred without the accumulation of reactive oxygen species that typically cause cellular exhaustion.
Presenting her findings at the annual meeting of the American Association of Immunologists, Gicobi received significant attention and excitement from attendees. The work opens up new possibilities for improving the health of T cells, which is crucial in cancer treatment.
However, further research is needed to understand how resilient T cells impact patient outcomes and why some individuals possess them while others do not. Dr. Dong also aims to explore the mechanisms underlying the function of resilient T cells and assess the potential of ME1 as a therapy.
Nevertheless, the discovery of resilient T cells represents a significant milestone in understanding the resilience of the body’s immune response. This finding has the potential to bring about new discoveries that can ultimately benefit patients facing cancer.
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1. Source: Coherent Market Insights, Public sources, Desk research
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