CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response
Menée notamment à l'aide d'échantillons de métastases prélevés, avant et après traitement, sur des patients atteints d'un cancer colorectal ou d'un adénocarcinome canalaire du pancréas avec microsatellites stables, cette étude démontre que l'inhibition du récepteur CXCR4 induit une réponse immunitaire
Patients with microsatellite stable (MSS) pancreatic (PDA) or colorectal cancer (CRC) do not respond to immunotherapy with inhibitors of T cell checkpoints. A possible explanation is suggested by finding that cancer cells in these tumors are coated with the chemokine, CXCL12, and that stimulation of CXCR4, the CXCL12 receptor on immune cells, suppresses directed migration mediated by other chemokine receptors on these cells. We assessed the relevance of these findings by treating patients for seven days with continuous infusion of AMD3100/Plerixafor, a CXCR4 inhibitor. Comparison of pre- and end-of-treatment paired biopsies of metastatic lesions by transcriptomic analysis revealed that AMD3100 induced an integrated immune response that is predictive of a clinical response to T cell checkpoint inhibition.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.All study data are included in the article and supporting information.