Oncogenic Vav1-Myo1f induces therapeutically targetable macrophage-rich tumor microenvironment in peripheral T cell lymphoma
José R. Cortés, Ioan Filip, Robert Alberó, Juan Ángel Patiño-Galindo, S. Aidan Quinn, Wen-Hsuan W. Lin, Anouchka P. Laurent, Bobby B. Shih, Jessie Brown, Anisha J. Cooke, Adam L. Mackey, Jonah Einson, Sakellarios Zairis, Alfredo Rivas‐Delgado, Maria Antonella Laginestra, Stefano Pileri, Elı́as Campo, Govind Bhagat, Adolfo A. Ferrando, Raúl Rabadán, Teresa Palomero
Abstract
Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) comprises heterogeneous lymphoid malignancies characterized by pleomorphic lymphocytes and variable inflammatory cell-rich tumor microenvironment. Genetic drivers in PTCL-NOS include genomic alterations affecting the VAV1 oncogene; however, their specific role and mechanisms in PTCL-NOS remain incompletely understood. Here we show that expression of Vav1-Myo1f , a recurrent PTCL-associated VAV1 fusion, induces oncogenic transformation of CD4 + T cells. Notably, mouse Vav1-Myo1f lymphomas show T helper type 2 features analogous to high-risk GATA3 + human PTCL. Single-cell transcriptome analysis reveals that Vav1-Myo1f alters T cell differentiation and leads to accumulation of tumor-associated macrophages (TAMs) in the tumor microenvironment, a feature linked with aggressiveness in human PTCL. Importantly, therapeutic targeting of TAMs induces strong anti-lymphoma effects, highlighting the lymphoma cells' dependency on the microenvironment. These results demonstrate an oncogenic role for Vav1-Myo1f in the pathogenesis of PTCL, involving deregulation in T cell polarization, and identify the lymphoma-associated macrophage-tumor microenvironment as a therapeutic target in PTCL.