Inflammatory reprogramming of the tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes in solid cancer

Abstract

Clonal hematopoiesis (CH) – the expansion of somatically-mutated hematopoietic cells in blood – is common in solid cancers. CH is associated with systemic inflammation that may lead to cancer, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naïve patient samples from the CPTAC cohort. CH was present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. The presence of CH-Tum was associated with worse survival across cancers, particularly for glioblastoma.Transcriptomics and proteomics revealed that CH drives inflammation in the TME in a cancer- and CH driver-specific manner, and may improve immunotherapy responses. In glioblastoma, CH associated with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.