Tumor-infiltrating clonal hematopoiesis is associated with NSCLC recurrence

1. In this retrospective cohort study, the presence of tumor-infiltrating clonal hematopoiesis (TI-CH) was associated with an increased risk of disease recurrence or death among patients with non-small-cell lung cancer (NSCLC).

2. Using preclinical mouse and organoid models of lung cancer, TI-CH was found to remodel the tumor immune microenvironment and accelerate tumor organoid growth.

Evidence Rating Level: 2 (Good)

Study Rundown: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition involving the expansion of blood cells derived from a somatically mutated hematopoietic stem cell in the absence of hematologic disorders. CHIP not only increases the risk of hematologic cancers, but is also associated with an increased incidence of lung cancer and increased risk of death among patients with solid tumors. Among patients with CHIP, CHIP-derived immune cells have been detected in solid tumor tissues, but the effect of these tumour-infiltrating immune cells with CHIP mutations, also known as TI-CH, on tumor progression and patient outcomes remains poorly understood. The present analysis determined the prevalence of TI-CH in patients with early-stage NSCLC and examined its associations with patient outcomes, including recurrence-free and overall survival. Among patients with NSCLC, those with CHIP were found to have shorter recurrence-free and overall survival than those without CHIP. Furthermore, preclinical models of lung cancer were used to explore how TI-CH exerts its effects, and TI-CH was found to remodel the tumor immune microenvironment and accelerate tumor organoid growth. Although these findings are based in part on preclinical models of cancer, which do not fully replicate the in vivo characteristics of the disease, these findings nonetheless provide insightful support other recent studies which have highlighted the role that the aging hematopoietic system plays in the development of lung cancer, with age-related hematologic clonal proliferation being shown to influence cancer progression.

Click to read the study in NEJM

In-Depth [retrospective cohort]: This study assessed the prevalence of TI-CH among 421 patients with previously untreated stage IA to IIIA NSCLC to identify associations between the presence of TI-CH and patient outcomes. Blood samples were obtained from participants, and CHIP was detected in blood with the use of a 2% variant-allele frequency (VAF) cutoff across 77 myeloid driver genes. CHIP mutations were observed in 34% of patients, with a median VAF of 5% (interquartile range, 3 to 11). The median recurrence-free survival was 2.7 years with CHIP (95% Confidence Interval, 2.0 to 5.0) compared with 6.0 years without CHIP (95% CI, 3.8 to not reached). The median overall survival was 4.0 years with CHIP (95% CI, 2.8 to not reached) compared with 6.0 years without CHIP (95% CI, 5.5 to not reached). To further examine how TI-CH exerts its effects in the evolution of cancer, mouse models and patient-derived lung adenocarcinoma organoids were developed using either TET2-mutant myeloid cells or wild-type myeloid cells. Using the mouse models, it was found that Tet2-mutant monocytes preferentially migrate toward lung cancer cells and accumulate in the tumor microenvironment. Additionally, co-cultures of tumor organoid cells with TET2-mutant myeloid cells resulted in larger and more numerous organoids compared to co-cultures with wild-type myeloid cells. Altogether, these preclinical models show that TI-CH remodels the tumor immune microenvironment and accelerates tumor organoid growth. In summary, TI-CH was shown to increase the risk of disease recurrence or death among patients with NSCLC. Evidence from preclinical models of lung cancer further elucidated the potential mechanism by which TI-CH exerts its actions, with TI-CH found to remodel the tumor immune microenvironment and accelerate tumor organoid growth.

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