Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer
Abstract
The survival benefit of antiangiogenic therapies for cancer patients has been limited, potentially due to intrinsic/acquired resistance. Deciphering and targeting resistance mechanisms are critical to improving treatment outcome, especially in cancers where antiangiogenic therapies are standard of care, such as colorectal cancer (CRC). Consistent with our clinical findings, we found up-regulation of CXCL12/CXCR4 in orthotopic CRC models and conditional Apc mutant spontaneous rectal tumors after anti-VEGFR2 treatment. CXCR4 signaling recruited immunosuppressive innate immune cells such as Ly6C low monocytes and Ly6G + neutrophils to the CRCs, conferring resistance to VEGFR2 blockade. Furthermore, we successfully targeted these pathways genetically and pharmacologically, including with an FDA-approved agent Plerixafor (AMD3100), which significantly enhanced treatment response. These strategies have the potential for rapid clinical translation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 12, 2017
- Source ID
- 10.1073/pnas.1710754114
Entities
People
- Andrew D. Luster
- Christopher G. Willett
- Dai Fukumura
- Elizabeth Y. Beech
- Euiheon Chung
- Jeffrey W. Clark
- Joao Incio
- Jun Ki Kim
- Keehoon Jung
- Kosuke Kawaguchi
- Matthias Pinter
- Nuh N. Rahbari
- Rakesh Jain
- SeokâHyun Yun
- Takahiro Heishi
- Timothy P Padera
- William W Ho
- Yuhui Huang
Organizations
- Duke University
- Harvard Medical School
- Harvard University
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institutes of Health
- United States Army