Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout (Tet2-/-) and floxed control mice (Tet2fl/fl) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2-/- mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2-/- mice. We delineated the transcriptional landscape of Tet2-/- neutrophils and found that, while inflammation-related pathways were upregulated in Tet2-/- neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by Tet2-/- neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

Clonal hematopoiesis of indeterminate potential-associated non-small cell lung cancer risk is potentiated by small particulate matter air pollution among non-smokers: a novel somatic variant-environment interaction.

Small particulate matter air pollution (PM 2.5 ) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smoking individuals. Inhaled PM 2.5 recruits pro-inflammatory macrophages to the air-lung interface, which promotes malignant lung epithelial cell growth and progression to overt cancer. We sought to determine whether clonal hematopoiesis of indeterminate potential (CHIP), a common age-related condition characterized by hyperinflammatory macrophages, exacerbates PM 2.5 -associated NSCLC in non-smokers using genetic, environmental, and phenotypic data from 413,901 individuals in the UK Biobank. Among non-smokers, PM 2.5 is not associated with NSCLC and not associated with prevalence of CHIP, but CHIP is associated with a doubling of NSCLC risk (hazard ratio (HR) 2.01, 95% confidence interval (CI): 1.34-3.00). Moreover, CHIP-associated NSCLC risk is exacerbated in the setting of above-median PM 2.5 levels (HR 2.70, 95% CI: 1.60-4.55). PM 2.5 × CHIP is also associated with significantly greater markers of systemic inflammation (CRP, IL-6, and IL-1ß) than expected. Altogether, these results suggest CHIP and PM 2.5 form a novel gene × environment interaction promoting NSCLC tumorigenesis in non-smokers.

Clonal Hematopoiesis: Updates and Implications at the Solid Tumor-Immune Interface.

Recent larger-scale studies of patients with cancer and longitudinal population cohorts have revealed how age-related expansions of mutant hematopoietic cells (clonal hematopoiesis [CH]) have differential associations with incident and prevalent cancers and their outcomes. Increasing recognition and deeper understanding of genetic subtypes of CH are yielding insights into the tumor-immune interface that may help to explain the heterogeneous impact of CH on tumorigenesis and treatment. Herein, we update the expanding influence of CH in precision oncology and propose important research and clinical questions to address to effectively manage and harness CH in oncology patients.