TET2 Mutations Enhance Cancer Immunotherapy Response in New Studies

Clonal hematopoiesis driven by TET2 mutations may enhance response to cancer immunotherapy, according to research published in Cancer Research. The study investigated the role of TET2-CH in promoting response to immune checkpoint blockade and found that in patients with colorectal cancer and melanoma, TET2-CH was associated with an immune-rich tumor microenvironment and greater odds of clinical benefit from immune checkpoint blockade.

In a model of hematopoietic Tet2 inactivation in mice implanted with syngeneic flank tumors, researchers found increased efficacy of anti-PD-1 immune checkpoint blockade, which required both myeloid and T cells. Mechanistically, Tet2-deficient T cells were biased toward memory states, curbing exhaustion and regulatory phenotypes, whereas myeloid cells shifted from immunosuppressive to costimulatory programs with PD-1 blockade.

The findings suggest that TET2-CH may serve as a biomarker of accentuated cancer immunotherapy response. Clonal hematopoiesis, marked by somatic mutations in a blood cell clone, is common in aging and is associated with an increased risk of future leukemia as well as nonhematologic diseases. In solid tumors, the presence of clonal hematopoiesis is linked to faster cancer progression and poor outcomes, yet its role in tumor immunity is complex.

Separate research at Université de Montréal has identified a molecule called SLAMF6 that may explain why some cancer immunotherapy treatments stop working over time. The team describes SLAMF6 as an internal brake on T cells, one that can activate on the T cell surface without needing to bind a tumor cell.

The researchers argue SLAMF6 can self-activate through homotypic cis interactions, meaning SLAMF6 molecules interact with each other on the same cell, sending a stop signal from within the T cell itself. In mouse experiments, T cells lacking SLAMF6 were more active after certain types of stimulation. They proliferated more and produced more cytokines in response to CD3 stimulation, with or without CD28.

When OT-I CD8+ T cells from Slamf6-deficient mice were transferred into tumor-bearing mice, tumor growth dropped compared with transfers using wild-type T cells. Those mice also had higher proportions of OT-I T cells and greater production of interferon-γ and tumor necrosis factor.

The group developed new monoclonal antibodies designed to prevent SLAMF6 from binding to itself. SLAMF6 mAb 21 reduced energy transfer by about 90%, and mAb 23 by about 80% in FRET assays. Those same antibodies drove much larger increases in human T cell activation responses.

In mice inoculated with E.G7 tumors, treatment with a potent blocking antibody reduced tumor growth compared with control antibodies. Tumors from treated mice showed more tumor-infiltrating OT-I T cells and higher interferon-γ and tumor necrosis factor. Blocking SLAMF6 shifted the balance away from TCF-1−TIM-3+ cells and toward TCF-1+TIM-3− cells, alongside changes in markers like PD-1, TOX, TIGIT, LAG-3, and TIM-3.

The study also explored combining SLAMF6 blockade with PD-L1 blockade in an MC-38 tumor model. Each treatment reduced tumor growth, and the combination produced the strongest effect in that setting. However, when Slamf6-deficient T cells were used in a graft-versus-host disease model, mice receiving those T cells had shorter survival and more weight loss.

In childhood brain cancer research, a study published in Nature Genetics identified a new immune pathway that could lead to less toxic treatments. Researchers in Cambridge looked at three models of childhood brain cancer: ependymoma, choroid plexus carcinoma and medulloblastoma.

The research team discovered a previously unknown immune communication pathway that exists outside the tumour. They observed that signals from the tumour travel through the cerebrospinal fluid to reach the brain's border tissues and skull bone marrow. There, they reprogramme immune cells, educating them not to attack. This enables the tumour to keep growing.

Researchers were able to block the tumour-derived signals using antibody treatments in their three models. The treatments prompted the immune system to recognise and attack the tumours, causing them to shrink and improving survival. The approach appears to have very few side effects.

Current treatment options for childhood brain cancers, including surgery, radiotherapy and chemotherapy, can have long term side effects that significantly impact quality of life. Immunotherapy holds promise as it tends to cause fewer side effects than traditional cancer treatments, but has so far had little success against brain cancers. Major obstacles include the complexity of these tumours, as well as difficulties crossing the blood-brain barrier to reach them.

Cancer Research UK and the Little Princess Trust supported the childhood brain cancer research. Further work is now needed to test whether this approach is safe and effective for children.