期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 46, 页码 28960-28970出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2013644117
关键词
pancreatic cancer; colorectal cancer; CXCR4; immunotherapy; AMD3100
资金
- National Institute for Health Research (NIHR) Cambridge Clinical Research Facility
- Human Research Tissue Bank
- NIHR Cambridge Biomedical Research Centre
- SU2C-Lustgarten Foundation Dream Team
- Cancer Research UK Institute [C14303/A17197, C9545/A29580]
- CK Hutchison Holdings Limited
- University of Cambridge
- Cancer Research UK [C14303/A17197, C9545/A29580, C42738/A24868]
- National Institutes of Health [5P30CA045508-31]
- Pershing Square Innovation Fund
- Experimental Medicine Initiative Clinical Lectureship
Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltra-tion and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with micro satellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
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