Christopher Groth1,2,3,4, Ludovica Arpinati5, Merav E Shaul5, Nina Winkler1,2,3, Klara Diester1,2,3, Nicolas Gengenbacher6,7, Rebekka Weber1,2,4, Ihor Arkhypov1,2, Samantha Lasser1,2,3, Vera Petrova1,2, Hellmut G Augustin6,7, Peter Altevogt1,2, Jochen Utikal1,2, Zvi G Fridlender5, Viktor Umansky1,2,4. 1. Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. 2. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany. 3. Faculty of Biosciences, Ruprecht-Karl University of Heidelberg, 69120 Heidelberg, Germany. 4. Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. 5. Institute of Pulmonary Medicine, Hebrew University Hadassah Medical Center, POB 12000, Jerusalem 9112001, Israel. 6. European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany. 7. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Abstract
BACKGROUND: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. METHODS: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. RESULTS: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. CONCLUSIONS: We provide evidence for the tumor-promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
BACKGROUND: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. METHODS: Using the RETtransgenicmelanomamouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RETtransgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. RESULTS: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. CONCLUSIONS: We provide evidence for the tumor-promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
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