Impact of Clonal Hematopoiesis on Solid Tumor Development and Response to Therapy

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Individuals with clonal hematopoiesis (CH) are at a significantly higher risk to develop solid tumors compared to age-matched non-CH carriers irrespective of prior therapy. While shared risk factors may contribute, the unique functions that CH- mutant hematopoietic cells play in solid tumor development remain unknown. Notably, CH carriers with mutations in the epigenetic regulator TET2 have a strong predilection for development of solid tumors such as lung cancer, underscoring a critical underexplored area of research with the potential to improve disease surveillance and treatment strategies. I hypothesize that Tet2-mutant hematopoietic cells play a critical role in tumor development by conditioning a favorable solid tumor environment into a conducive landscape for CH-mutant cell growth and proliferation. Aim 1 of this proposal will quantify the impact of Tet2- mutant hematopoietic cells on lung-specific tumor development and response to radiation therapy (RT) as Tet2 mutations are frequently found in solid tumors and lung cancer is among the most frequent solid cancer type to arise in a CH background. Building on preliminary data which displayed enhanced tumor growth in a Tet2-mutant background, I will create chimeric mice with a Tet2-mutant hematopoietic system followed with establishment of solid lung-specific tumors. After determining normal tumor growth and metastatic patterns, targeted RT will be utilized to capture tumor volumetric response to therapy. Aim 2 will identify the spectrum of CH-mutant immune cells that infiltrate the tumor and define the role(s) they play in the tumor microenvironment (TME). Pilot experiments revealed overrepresented tumor infiltration of Tet2-mutant monocytes. I will investigate these target cell populations by conditional activation and deletion in genetic mouse models to address if specific, mutant cell populations enhance tumor development. In parallel, tumor infiltrating monocytes will be evaluated for aberrant transcriptional statuses and could provide attractive targets to mitigate solid tumor growth/resistance to therapy. Aim 3 will evaluate the cytokine profiles within solid tumors and how this environment uniquely shifts in the presence of Tet2-mutant hematopoietic cells. Pilot studies reproduced known aberrant cytokine levels induced by TET2 CH in humans, with TNFα emerging as a highly upregulated cytokine which further proved amenable to pharmacological reduction in preliminary experiments. The primary focus will be on the impact of TNFα neutralization on tumor burden, while a comprehensive cytokine profiling will ensure no potential therapeutic targets are overlooked. This project will address a knowledge gap that affects a large patient population who develop solid tumors with a background of CH mutations. The results of this research proposal will identify new insights into the function of CH-mutant cells and how they drive solid tumor development which could unveil pivotal mechanisms offering new avenues for targeted therapies and intervention strategies.