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

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Biasci, Daniele 
Smoragiewicz, Martin  ORCID logo
Gao, Ya 


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.



AMD3100, CXCR4, colorectal cancer, immunotherapy, pancreatic cancer, Aged, Benzylamines, Carcinoma, Pancreatic Ductal, Chemokine CXCL12, Colorectal Neoplasms, Cyclams, Female, Heterocyclic Compounds, Humans, Immunity, Immunotherapy, Male, Middle Aged, Pancreas, Pancreatic Neoplasms, Receptors, CCR2, Receptors, CXCR3, Receptors, CXCR4, Receptors, CXCR5, Receptors, CXCR6, Receptors, Interleukin-8A, Signal Transduction, Tumor Microenvironment

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Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences
American Association for Cancer Research (AACR) (via Johns Hopkins University) (unknown)
European Commission Horizon 2020 (H2020) Societal Challenges (633974)
Cancer Research UK (C14303/A17197)
Medical Research Council (MR/L006197/1)
Stand Up 2 Cancer, Lustgarten Foundation, NIHR