Jung Keehoon, Heishi Takahiro, Khan Omar F, Kowalski Piotr S, Incio Joao, Rahbari Nuh N, Chung Euiheon, Clark Jeffrey W, Willett Christopher G, Luster Andrew D, Yun Seok Hyun, Langer Robert, Anderson Daniel G, Padera Timothy P, Jain Rakesh K, Fukumura Dai
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA.
David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
J Clin Invest. 2017 Aug 1;127(8):3039-3051. doi: 10.1172/JCI93182. Epub 2017 Jul 10.
Current anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6Clo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6Clo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6Clo monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clo monocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6Clo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6Clo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies.
目前用于治疗结直肠癌（CRC）的抗血管内皮生长因子（VEGF）疗法对延长生存期的益处有限，因为肿瘤会迅速对这些药物产生耐药性。在此，我们发现了非经典Ly6Clo单核细胞的免疫抑制作用，它介导了对抗血管内皮生长因子受体2（VEGFR2）治疗的耐药性。我们发现，在VEGF信号通路被阻断后，趋化因子CX3CL1在人类和小鼠肿瘤中均上调，导致CX3CR1+Ly6Clo单核细胞募集到肿瘤中。我们还发现，体外使用血管内皮生长因子A（VEGFA）处理可降低内皮细胞中CX3CL1的表达。活体显微镜检查显示，CX3CR1对于Ly6Clo单核细胞在小鼠结直肠癌肿瘤中穿过内皮的迁移至关重要。此外，Ly6Clo单核细胞通过CXCL5募集Ly6G+中性粒细胞并产生白细胞介素10（IL-10），从而抑制适应性免疫。阻止Ly6Clo单核细胞或Ly6G+中性粒细胞浸润到肿瘤中可增强抗VEGFR2疗法对肿瘤生长的抑制作用。此外，一种使用针对CX3CL1的小干扰RNA（siRNA）配制的纳米颗粒进行的基因疗法减少了Ly6Clo单核细胞的募集，并改善了抗VEGFR2疗法在小鼠结直肠癌中的治疗效果。我们的研究揭示了Ly6Clo单核细胞的免疫抑制功能，据我们所知，这在任何情况下均尚未见报道。我们还揭示了抗血管生成治疗耐药性的分子机制，提示了潜在的免疫调节策略，以提高抗VEGF疗法的长期临床疗效。
