Gene mutation in blood-forming cells may improve cancer immunotherapy results

Researchers at UHN’s Princess Margaret Cancer Centre have found that inactivation of the TET2 (Tet methylcytosine dioxygenase 2) gene in immune cells improves the response of immunotherapy — a type of treatment that helps the immune system attack cancer cells — in certain cancer models. These results could lead to a marker that predicts how well immunotherapy for cancer will work.

TET2 is an important regulator of gene expression and is frequently altered in clonal hematopoiesis (CH), a condition in which a mutated blood stem cell makes many identical copies of itself. Although CH can lead to cancers such as leukemia, it is still unclear how CH affects tumour biology, cancer outcomes, and response to treatments, such as immunotherapy. TET2 inactivation is associated with improved function of immunotherapy involving T-cells — immune cells that find and destroy infected or abnormal cells — and can boost immunity.

These links to immunity led the research team to investigate how TET2 mutations impact responses to cancer immunotherapy approaches like immune checkpoint blockade (ICB), in which drugs inhibit proteins that are normally responsible for keeping the immune system in check. This then enables immune cells to kill cancer cells.

Using preclinical cancer models, the study found that TET2 mutations in blood-forming cells enhanced the ICB response, but only in the presence of special immune cells that help fight infections and cancer, including phagocytes, CD4+ T-cells and CD8+ T-cells. TET2-mutant immune cells respond to ICB therapy by shifting away from tumour-promoting states toward tumour-fighting states. This mutation led to the activation of T-cells and led to the development of stronger “memory” to recognize cancer in some immune cells, along with fewer signs of fatigue or suppression in these cells.

Clinical data reinforced these findings: tumours from colorectal cancer and melanoma patients with TET2-related CH showed higher immune activity. In melanoma patients receiving ICB, those with TET2 mutations were six times more likely to benefit from treatment.

These results suggest TET2 mutations could serve as a marker for personalized immunotherapy, potentially guiding treatment decisions in the future. A deeper understanding of how TET2 inactivation improves immunotherapy responses could someday lead to new, synergistic treatments.