Cancer dysregulates the complex structure of tissues and internal cellular pathways. As a result, the immune system loses its ability to effectively target tumor cells. The immune system is made up of two barriers of protection against pathogens and deleterious infections. Specifically, the innate and adaptive immune responses work together to provide effective immunity. The innate immune system is the first responder to any unfamiliar pathogen. It is a general response to minimize spread to other areas and can only handle low-scale infections. Adaptive immunity refers to a specific, robust response that comes in after the innate immune system. Adaptive immune cells consist of T and B cells, which target and neutralize disease more directly and efficiently. Together, the two regulate an immune response to efficiently eliminate disease.
Special T cells known as ‘CD8+ T cells’ are responsible for directly identifying and targeting infected cells. In the context of cancer, these cells lose their function and allow tumors to progress. However, these cells which are deemed ‘exhausted’ around the tumor, are comprised of a mix of various cells at different stages of life. Younger cells are more malleable or ‘stem-like’, while older cells are differentiated and have trouble adapting to their environments. These younger cells are referred to as ‘progenitor cells’. Unfortunately, it is unclear how different subsets of CD8+ T cells occur, particularly around the tumor.
A recent article in Nature Communications, by Dr. Lewis Shi and others, demonstrate how immunotherapy can be improved by targeting a protein in CD8+ T cells. Specifically, Shi and his team determined that intermittent inhibition of a protein known as growth factor independent-1 (Gfi1) differentiates T cells and reduces their exhaustion. Shi is a Professor and Director of Radiobiology at the University of Alabama Birmingham. He is also the Koikos-Petelos-Jones-Bragg ROAR Endowed Professor for Cancer Research for his work on radiation oncology. Specifically, Shi and his team focus on improving immunotherapies by studying T cell biology. His work has garnered international attention and has identified key signaling mechanisms critical in T cell immune response.
Shi and his team tried to better understand how to regulate exhaustion in T cells during chronic infection. The researchers used various laboratory techniques, including mouse models, to analyze chronically inflamed, exhausted T cells. To identify the specific role of this protein, the team knocked out Gfi1 in T cells and compared it to Gfi1 expressing cells. Surprisingly, the T cells with Gfi1 expression were more differentiated or mature with a stronger anti-tumor function. However, overexpression of Gfi1 did not reduce exhaustion. Therefore, the team concluded that transient and low expression of Gfi1 is necessary to improve T cell fitness and improve immunotherapy.
Shi and his team have made a groundbreaking discovery. They have identified Gfi1 as a key regulator in exhausted CD8+ T cells. As a result, they have a way to improve immunotherapy currently available in the clinic against solid tumors. Further work needs to be conducted in clinical trials; however, this work has the potential to significantly improve cancer care and prolong survival in patents with solid tumors.
Article, Nature Communications, Lewis Shi, University of Alabama Birmingham