TET2-Mutant Clonal Hematopoiesis Enhances Macrophage Antigen Presentation and Improves Immune Checkpoint Therapy in Solid Tumors

Authors

Shelley Herbrich
Mehdi Chaib
Swetha Anandhan
Samuel W Andrewes
Ashwat Nagarajan
Baoxiang Guan
Nishant Gandhi
Jared Gilliam
Milan Radovich
Padmanee Sharma

Language

English

Publication Date

1-12-2026

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.09.011

PMID

41106379

Abstract

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients, TET2-mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2+/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2-mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.

Keywords

Dioxygenases, Animals, Humans, Mice, DNA-Binding Proteins, Clonal Hematopoiesis, Proto-Oncogene Proteins, Tumor Microenvironment, Macrophages, Immune Checkpoint Inhibitors, Antigen Presentation, Mutation, Mice, Inbred C57BL, Female, Neoplasms, Colorectal Neoplasms, CD8-Positive T-Lymphocytes, Carcinoma, Non-Small-Cell Lung, TET2, antigen presentation, clonal hematopoiesis, cross-priming, immune checkpoint therapy, tumor immunology

Published Open-Access

yes

Recommended Citation

Herbrich, Shelley; Chaib, Mehdi; Anandhan, Swetha; et al., "TET2-Mutant Clonal Hematopoiesis Enhances Macrophage Antigen Presentation and Improves Immune Checkpoint Therapy in Solid Tumors" (2026). Faculty, Staff and Student Publications. 6510.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6510