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

Published version
Peer-reviewed

Type

Article

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Authors

Biasci, Daniele 
Smoragiewicz, Martin  ORCID logo  https://orcid.org/0000-0002-4934-6323
Gao, Ya 

Abstract

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.

Description

Keywords

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

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

117

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
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