CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

Biasci, D., Smoragiewicz, M., Connell, C. M., Wang, Z., Gao, Y., Thaventhiran, J. E. D., Basu, B., Magiera, L., Johnson, T. I., Bax, L., Gopinathan, A., Isherwood, C., Gallagher, F. A., Pawula, M., Hudecova, I., Gale, D., Rosenfeld, N., Barmpounakis, P., Popa, E. C., Brais, R., Godfrey, E., Mir, F., Richards, F. M., Fearon, D. T., Janowitz, T., Jodrell, D. I. (November 2020) CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc Natl Acad Sci U S A, 117 (46). pp. 28960-28970. ISSN 0027-8424 (Print)0027-8424

DOI: 10.1073/pnas.2013644117


Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration 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 CXCL12-stimulated 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 microsatellite 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.

Item Type: Paper
Additional Information: 1091-6490 Biasci, Daniele Smoragiewicz, Martin Orcid: 0000-0002-4934-6323 Connell, Claire M Orcid: 0000-0002-6696-8415 Wang, Zhikai Orcid: 0000-0002-8565-6011 Gao, Ya Thaventhiran, James E D Orcid: 0000-0001-8616-074x Basu, Bristi Magiera, Lukasz Johnson, T Isaac Bax, Lisa Gopinathan, Aarthi Isherwood, Christopher Gallagher, Ferdia A Orcid: 0000-0003-4784-5230 Pawula, Maria Hudecova, Irena Gale, Davina Rosenfeld, Nitzan Barmpounakis, Petros Orcid: 0000-0002-1020-3886 Popa, Elizabeta Cristina Brais, Rebecca Godfrey, Edmund Mir, Fraz Richards, Frances M Orcid: 0000-0001-7947-7853 Fearon, Douglas T Janowitz, Tobias Orcid: 0000-0002-7820-3727 Jodrell, Duncan I P30 CA045508/CA/NCI NIH HHS/United States C14303/A17197/CRUK_/Cancer Research UK/United Kingdom C9545/A29580/CRUK_/Cancer Research UK/United Kingdom C42738/A24868/CRUK_/Cancer Research UK/United Kingdom DH_/Department of Health/United Kingdom Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28960-28970. doi: 10.1073/pnas.2013644117. Epub 2020 Oct 30.
Uncontrolled Keywords: *amd3100 *cxcr4 *colorectal cancer *immunotherapy *pancreatic cancer validation of the pharmacokinetics assay, but had no part in study design, data acquisition, data analysis, or manuscript preparation. N.R. and D.G. are co-founders, shareholders, and officers or consultants of Inivata Ltd., a cancer genomics company that commercializes ctDNA analysis. Inivata had no role in the conceptualization, study design, data collection and analysis, decision to publish, or preparation of the manuscript.
CSHL Authors:
Communities: CSHL labs > Fearon lab
CSHL labs > Janowitz lab
Depositing User: Matthew Dunn
Date: 17 November 2020
Date Deposited: 19 Apr 2021 22:04
Last Modified: 19 Apr 2021 22:04
PMCID: PMC7682333
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