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.
Dr. Vincent Rondeau, Postdoctoral Researcher at Princess Margaret Cancer Centre, is the first author of the study.
Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre, University Professor at the University of Toronto, Helga and Antonio De Gasperis Chair in Blood Cancer Stem Cell Research, and Professor in the Department of Molecular Genetics at the University of Toronto, is the co-corresponding author of the study.
Dr. Robert Vanner, Affiliate Scientist at Princess Margaret Cancer Centre, Clinician Scientist in the Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, and Assistant Professor at the Institute for Medical Science at the University of Toronto, is the co-corresponding author of the study.
This work was supported by Merck Canada Inc., the Leukemia & Lymphoma Society of Canada, the Canadian Institutes for Health Research, the PSI Foundation, the Douglas Wright Foundation, The German Cancer Research Center, the Ontario Institute for Cancer Research, Terry Fox Research Institute, the Canadian Cancer Society, the Government of Ontario, the Ontario Ministry of Health, the Canada Research Chairs program, and The Princess Margaret Cancer Foundation.
Dr. Robert Vanner and Dr. John Dick are co-inventors of a patent, ‘Clonal Hematopoiesis as a Biomarker’. Dr. Dick receives revenue from patents licenced to Trillium Therapeutics Inc/Pfizer and receives a commercial research grant from Celgene/BMS.
Rondeau V, Bansal S, Buttigieg MM, Zeng AGX, Chan DY, Chan-Seng-Yue M, Jin L, McLeod J, Kates M, Donato E, Stelmach P, Vlasschaert C, Yang Y, Gupta A, Genta S, Sanz-Garcia E, Shlush L, Ribeiro M, Butler MO, Abelson S, Minden MD, Saibil SD, Chan SM, Rauh MJ, Trumpp A, Dick JE, Vanner RJ. Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation. Cancer Res. 2025 Nov 11. doi: 10.1158/0008-5472.CAN-24-3329. Epub ahead of print.