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

Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28960-28970. doi: 10.1073/pnas.2013644117. Epub 2020 Oct 30.

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.

Keywords: AMD3100; CXCR4; colorectal cancer; immunotherapy; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Pancreatic Ductal
  • Chemokine CXCL12
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Heterocyclic Compounds / antagonists & inhibitors
  • Humans
  • Immunity / immunology*
  • Immunotherapy
  • Male
  • Middle Aged
  • Pancreas / metabolism*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Receptors, CCR2 / metabolism
  • Receptors, CXCR3 / metabolism
  • Receptors, CXCR4 / drug effects*
  • Receptors, CXCR4 / metabolism*
  • Receptors, CXCR5 / metabolism
  • Receptors, CXCR6 / metabolism
  • Receptors, Interleukin-8A / metabolism
  • Signal Transduction / drug effects
  • Tumor Microenvironment / immunology

Substances

  • CCR2 protein, human
  • CXCL12 protein, human
  • CXCR3 protein, human
  • CXCR4 protein, human
  • CXCR5 protein, human
  • CXCR6 protein, human
  • Chemokine CXCL12
  • Heterocyclic Compounds
  • Receptors, CCR2
  • Receptors, CXCR3
  • Receptors, CXCR4
  • Receptors, CXCR5
  • Receptors, CXCR6
  • Receptors, Interleukin-8A
  • plerixafor

Supplementary concepts

  • Pancreatic Carcinoma