title: Aptamer-mediated blockade of IL4Rα triggers apoptosis of MDSCs and limits tumor progression.
abstract: In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-α (IL4Rα or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Rα aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Rα signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Rα signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer.
authors.affiliation: Department of Microbiology and Immunology, Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Roth
authors.forename: Adriana C
authors.initials: AC
authors.lastname: De La Fuente
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Vella
authors.forename: Alessia
authors.initials: A
authors.lastname: Zoso
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Serafini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology
chemical_list: D052157:Aptamers, Nucleotide; C504000:IL4R protein, human; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse