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.
Highlights
Myeloid-derived suppressor cells (MDSC, CD11bþGr1þIL4Raþ [1, 2] and tumor-associated macrophages (TAM, CD11bþGr1ÀF4/80þ; ref. 3) are important in promoting tumor growth metastasis and angiogenesis [4, 5] and in suppressing the antitumor immune response [6]
We have previously shown that IL4Ra (CD124) is upregulated in many murine tumors and that it plays a key role in myeloidderived suppressor cells (MDSC) suppressive function in the mouse CT26 colon carcinoma [2] and A20 lymphoma [15]
MDSCs and tumor-associated macrophages in mice bearing the 4T1 mammary carcinoma We evaluated whether the IL4Ra–specific aptamer can bind its ligand in vivo and if preferential targeting of cell subset occurs in tumor-bearing mice
Summary
Myeloid-derived suppressor cells (MDSC, CD11bþGr1þIL4Raþ [1, 2] and tumor-associated macrophages (TAM, CD11bþGr1ÀF4/80þ; ref. 3) are important in promoting tumor growth metastasis and angiogenesis [4, 5] and in suppressing the antitumor immune response [6]. 3) are important in promoting tumor growth metastasis and angiogenesis [4, 5] and in suppressing the antitumor immune response [6]. Different signaling pathways may be responsible for the MDSC suppressive activity, the IL4Ra–STAT6 pathway seems to be important: it mediates TGF-b production [7], arginase activity [8] and, in conjunction with STAT3 and STAT1 activation, it allows for the production of peroxynitrite and ROS [6] and for the expression of matrix metalloproteinase 9 [9]. 10) and Authors' Affiliations: 1Department of Microbiology and Immunology, Sylvester Cancer Center, Miller School of Medicine, University of Miami; and 2Diabetes Research Institute, University of Miami Leonard M.
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