In a new study, Mass General Brigham researchers explore the causes of immune ageing, a barrier to successful cancer immunotherapy, and identify a gene that may serve as an age-related prognostic marker and potential target for future cancer therapies.

Alex C. Y. Chen, PhD, and Debattama (Deb) Sen, PhD, of the Mass General Brigham Cancer Institute, are the lead and senior authors, respectively, of the paper published in Cell.

Q: What challenges or unmet needs make this study important?

As a person gets older, their immune system becomes worse at fighting disease.

This age-related immune decline, also known as immune ageing, is a critical barrier to successful cancer immunotherapy.

However, we still do not fully understand what causes immune ageing, making it difficult to identify drug targets that could help overcome this barrier.

Q: What central question(s) were you investigating?

In our prior work, we found that the aged tumour microenvironment (TME) pushes CD8+ killer T cells toward dysfunction, reducing their ability to fight cancer.

Therefore, our goal is to identify new ways to reinvigorate CD8+ killer T cells in the TME and make them more effective by improving their persistence and tumour-killing capacity.

Q: What methods or approach did you use?

To achieve this goal, we performed a “CRISPR pooled screen,” making changes in multiple genes simultaneously to figure out the best possible target rather than studying genes one at a time.

This approach allows us to identify the regulators of T cell dysfunction within the aged TME in a scalable and efficient way.

We developed this screening method using aged tumour-bearing mice, whose tumour microenvironment closely mimics what tumour cells and T cells encounter in older cancer patients.

Q: What did you find?

Our results suggest that dual specificity phosphatase 5 (Dusp5) and zinc finger protein 219 (Zfp219) are two key regulators of T cell dysfunction, which leads to poor tumour control in aged hosts.

Dusp5 acts as a “brake” on ERK signalling pathways that help T cells increase in number.

When Dusp5 is removed, ERK signalling becomes more active, allowing T cells to proliferate more effectively.

Zfp219 acts as an "off switch" for genes involved in producing granzymes, tumour-fighting enzymes.

When Zfp219 is knocked out, T cells increase secretion of granzymes (e.g., GZMA, GZMB), making them better at killing tumour cells.

Q: What are the real-world implications, particularly for patients?

We found that older adults have higher levels of ZNF219, the human counterpart of the mouse gene Zfp219, in T cells within their tumours.

Higher ZNF219 levels were also associated with poorer responses to immune checkpoint blockade and shorter survival, likely because these T cells do not efficiently kill tumour cells.

Therefore, ZNF219 could serve as a new age-related prognostic marker for cancer patients.

Moreover, blocking ZNF219 activity could be a promising approach to improving T cell function as a cancer treatment for older adults.

Although ZNF219 itself is difficult to target with drugs, newer approaches that genetically modify a patient's own T cells, such as CAR-T cell therapy or other engineered T cell treatments, may provide a practical way to reduce ZNF219 activity and strengthen the body's ability to fight cancer.

Authorship: In addition to Chen and Sen, Mass General Brigham authors include Keely Ji, Cansu Yerinde, Nelson Knudsen, Kevin Bi, Shumeng Hao, Daniela Martinez, Thomas Carmona-LaSalle, Kazuhiro Taguchi, Katherine Xu, Elizabeth Seider, Maria Zschummel, Linda Nieman, Kathleen Yates, Francesca Gazzaniga, Thorsten Mempel, Robert Manguso and Nir Hacohen.

Additional authors include Vasyl Zhabotynsky, Marc Schwartz and Brian Miller.

Source: Mass General Brigham