文章基本信息

标题：Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer
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作者：Keehoon Jung ; Takahiro Heishi ; Joao Incio 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：39
页码：10455-10460
DOI：10.1073/pnas.1710754114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6C^low monocytes and not Ly6C^high monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6C^low monocytes ( Cx3cr1 ^−/− mice), Ly6C^high monocytes ( CCR2 ^−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6C^low monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G⁺ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6C^low monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.
关键词：tumor microenvironment ; CXCR4 ; Ly6C^low monocyte ; tumor immunity ; antiangiogenic therapy