| First Author | Rondeau V | Year | 2026 |
| Journal | Cancer Res | Volume | 86 |
| Issue | 4 | Pages | 845-857 |
| PubMed ID | 41218172 | Mgi Jnum | J:391221 |
| Mgi Id | MGI:8332386 | Doi | 10.1158/0008-5472.CAN-24-3329 |
| Citation | Rondeau V, et al. (2026) Response to Immune Checkpoint Blockade Is Enhanced in the Presence of Hematopoietic TET2 Inactivation. Cancer Res 86(4):845-857 |
| abstractText | Somatic mutations inactivating Tet methylcytosine dioxygenase 2 (TET2) are among the most common drivers of clonal hematopoiesis (CH). TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen receptor T-cell function, suggesting that it might also affect immunotherapy response. In this study, we found that hematopoietic Tet2 mutation in mouse models enhanced the immune checkpoint blockade (ICB) response, which required the combined presence of phagocytes, CD4+, and CD8+ T cells. The effect was lost with myeloid- or T-cell-restricted Tet2 inactivation or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes, ICB preferentially restricted cell states linked to tumor progression while inducing antitumor states. Tet2-mutant monocytes activated costimulatory programs, whereas Tet2-mutant T cells showed enhanced T-cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. Clinically, tumors from patients with colorectal cancer and melanoma with TET2-mutant CH showed enhanced immune infiltration, inflammation, and T-cell activation. In patients with melanoma treated with ICB, TET2-mutant CH was associated with six-fold greater odds of clinical benefit. Collectively, this work demonstrates that hematopoietic TET2 inactivation primes leukocytes for antitumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy. SIGNIFICANCE: TET2 mutations promote antitumor leukocyte states that can potentiate the efficacy of immunotherapy with checkpoint blockade. See related commentary by Yuan and Guryanova, p. 825. |
