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@ARTICLE{Rondeau:305751,
author = {V. Rondeau and S. Bansal and M. M. Buttigieg and A. G. X.
Zeng and D. Y. Chan and M. Chan-Seng-Yue and L. Jin and J.
McLeod and M. Kates and E. Donato$^*$ and P. Stelmach$^*$
and C. Vlasschaert and Y. Yang and A. Gupta and S. Genta and
E. Sanz-Garcia and L. Shlush and M. Ribeiro and M. O. Butler
and S. Abelson and M. D. Minden and S. D. Saibil and S. M.
Chan and M. J. Rauh and A. Trumpp$^*$ and J. E. Dick and R.
Vanner$^*$},
title = {{R}esponse to {I}mmune {C}heckpoint {B}lockade is
{E}nhanced in the {P}resence of {H}ematopoietic {TET}2
{I}nactivation.},
journal = {Cancer research},
volume = {86},
number = {4},
issn = {0099-7013},
address = {Philadelphia, Pa.},
publisher = {AACR},
reportid = {DKFZ-2025-02371},
pages = {845-857},
year = {2026},
note = {2026 Feb 16;86(4):845-857 / DKFZ-ZMBH Alliance / #LA:A010#},
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.},
cin = {A010 / HD01},
ddc = {610},
cid = {I:(DE-He78)A010-20160331 / I:(DE-He78)HD01-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41218172},
doi = {10.1158/0008-5472.CAN-24-3329},
url = {https://inrepo02.dkfz.de/record/305751},
}