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

The immune system has evolved to defend against infection while minimizing damage to non-infected tissues, which poses a major challenge for anti-cancer immunotherapy development. Cancer cells derived from human epithelia, such as colorectal and pancreatic cancer cells, are coated with CXCL12. Here, we find that in human immune cell-based chemotaxis assays, CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by different immune cell types that participate in integrated immune responses. Inhibiting CXCR4 in an experimental medicine study by one-week continuous infusion of the small molecule inhibitor, AMD3100, induces an integrated immune response detected by transcriptional analysis 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 non-infected tissues: rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, cancer immunotherapy may be improved by inhibiting the suppressive effects of CXCR4 on immune cell trafficking.