Journal Article

DKFZ-2025-02371

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.

Rondeau, V. ; Bansal, S. ; Buttigieg, M. M. ; Zeng, A. G. X. ; Chan, D. Y. ; Chan-Seng-Yue, M. ; Jin, L. ; McLeod, J. ; Kates, M. ; Donato, E.DKFZ* ; Stelmach, P.DKFZ* ; Vlasschaert, C. ; Yang, Y. ; Gupta, A. ; Genta, S. ; Sanz-Garcia, E. ; Shlush, L. ; Ribeiro, M. ; Butler, M. O. ; Abelson, S. ; Minden, M. D. ; Saibil, S. D. ; Chan, S. M. ; Rauh, M. J. ; Trumpp, A.DKFZ* ; Dick, J. E. ; Vanner, R. (Last author)DKFZ*

2026
AACR Philadelphia, Pa.

Abstract: Somatic mutations inactivating 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 it might also impact immunotherapy response. Here, 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 (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. Clinically, tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, this work demonstrates that hematopoietic TET2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

Note: 2026 Feb 16;86(4):845-857 / DKFZ-ZMBH Alliance / #LA:A010#

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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