PIM kinase inhibition attenuates pro-tumoral and immunosuppressive functions of macrophages in classic Hodgkin lymphoma.

Tumor-associated macrophages (TAMs) of classic Hodgkin Lymphoma (cHL) contribute to the development of immunosuppressive tumor microenvironment (TME) and are associated with worse treatment outcomes. However, detailed features, functions and therapeutic vulnerabilities of cHL TAMs remain largely unknown. To address this, we analyzed cHL diagnostic biopsies by Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and assessed transcriptional, proteomic and metabolic profiles of in vitro TAM models. We show that Reed-Sternberg (RS) cells induce a disease-specific TAM phenotype, characterized by elevated expression of factors involved in chemotaxis, angiogenesis, extracellular matrix remodeling and tumor immune escape. RS cell-conditioned TAMs expressed TGFβ, CCL17 and tryptophan catabolizing enzymes, IDO1 and IL4I1, promoting regulatory T cell recruitment and activation. In addition, we identified the expression of PIM1/2/3 kinases in cHL TAMs and characterized PIMs as critical hubs orchestrating RS-macrophage interactions. Pharmacological PIM blockade attenuated the RS-induced TAM transcriptional program. In established TAMs, PIM inhibition or PROTAC-mediated degradation decreased the expression of multiple factors associated with pro-tumoral TAM functions, including IL8, MMP9, CHI3L1/2, CD206, CD209, PD-L1, CCL17, TGFβ, IL4I1 and IDO1. PIM blockade attenuated TAM-dependent eosinophil chemoattraction, extracellular matrix remodeling, angiogenesis and regulatory T-cell development. Taken together, our study highlights the role of PIMs in the regulation of pathogenic TAM functions in cHL, further supporting the rationale of PIM targeting in this disease.