Abstract 2552: <i>TET2</i>-mutant clonal hematopoiesis enrichment in the tumor microenvironment is an actionable driver of treatment resistance in solid tumors: Thyroid cancer as a paradigm

Abstract Recurrent mosaic somatic mutations in circulating leukocytes can be frequently found in the aging population. These mutations frequently arise in epigenetic modifier genes like TET2. In the absence of signs of hematologic malignancies this condition is termed clonal hematopoiesis (CH). Although CH has been associated with increased incidence and adverse outcomes in patients with solid tumors, the disease-specific effects and mechanisms by which CH alters solid tumor biology have not been delineated. To develop insights into the interplay between mutant CH clones and epithelial tumor cells we analyzed a cohort of over forty-seven thousand patients who underwent paired blood and tumor sequencing. After correcting for age, sex, ancestry, stage, smoking, and previous treatment history, we identify unique patterns of poor survival associated with specific CH genotypes and solid tumor histologies. Given that the detection of tumor-infiltrating TET2-CH clones is especially associated with poorer outcomes in thyroid cancer patients (HR 2.18, 95%CI 1.18-4.05, p=0.013), we focused on studying the role of CH in thyroid cancer biology. Compared to other CH alleles, TET2-mutant CH is enriched in the tumor microenvironment (TME) across solid tumors and is associated with adverse prognosis specifically in Anaplastic thyroid cancer (ATC) patients. ATC is a clinically aggressive malignancy with a dismal prognosis. Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients with BRAFV600E-mutant ATCs. However, relapses are common and overall survival remains poor. A hallmark of ATC is significant infiltration with myeloid cells, particularly macrophages. ATCs are most common in the aging population, which also has an increased incidence of TET2-mutant CH. These mutant macrophages have been shown to accelerate CH-associated pathophysiology including atherosclerosis. However, the clinical and mechanistic contribution of TET2-mutant clones to the prognosis and/or treatment response in solid tumors has not been elucidated. Using subclonal murine models of Tet2-mutant CH we confirm that mutant macrophages selectively infiltrate mouse BrafV600E-mutant ATC models (58% higher enrichment of Tet2-/- cells in the TME compared to the WT counterparts) and confer resistance to BRAF/MEK inhibition (68-days median survival compared to no mortality after 147 days). Using single-cell CITEseq, we identify that the overexpression of Tgfβ-family ligands by CH macrophages is the driver of this resistance. Importantly, inhibition of Tgfβ signaling or the depletion of mutant-macrophages completely restored the sensitivity to MAPK pathway inhibition. In summary, this work identified a novel actionable resistance mechanism mediated by a clonally driven process within the tumor-immune microenvironment. Citation Format: Pablo Sanchez Vela, Vera Tiedje, Julie L. Yang, Brian R. Untch, Laura Boucai, Aaron J. Stonestrom, Alberto Bueno Costa, Sebastià Franch Expósito, Sebastià Franch Expósito, Avi Srivastava, Marina Kerpelev, Jillian Greenberg, Matthew Wereski, Amanda Kulick, Kevin Chen, Tianyue Qin, Soo-Yeon Im, Anthony R. Martinez Benitez, Raquel Pluvinet, Merve Sahin, Kamal Menghrajani, Gnana P. Krishnamoorthy, Elisa de Stanchina, Ahmet Zehir, Rahul Satija, Jeffrey Knauf, Robert L. Bowman, Manel Esteller, Sean Devlin, Michael F. Berger, Richard P. Koche, Ross L. Levine, James A. Fagin. TET2-mutant clonal hematopoiesis enrichment in the tumor microenvironment is an actionable driver of treatment resistance in solid tumors: Thyroid cancer as a paradigm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2552.