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

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.

The ratio of exhausted to resident infiltrating lymphocytes is prognostic for colorectal cancer patient outcome

“…GPR15, one of our CD8_Res markers, which also has restricted expression in Res CD4 and NK cells, is a GPCR involved in T cell trafficking in colon, and its expression in Tregs is promoted by TGF-β, mediating the suppression of inflammation in the colon [40]. CXCR4, identified as one of our CD4_Res genes involved in GPCR signalling, was just recently suggested to mediate immune suppression in pancreatic and CRC samples, and the use of anti-CXCR4 in MSS samples increased the immune response [64].…”

Life-long passion for antiviral research and drug development: 80th birthday of Prof. Dr. Erik De Clercq

“…In addition to its approved applications for multiple myeloma or non-Hodgkin’s lymphoma, plerixafor has also been considered for the treatment of many diseases such as warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome [86] , glioblastoma [87] , colorectal and pancreatic cancer [88] , leukemia [89] , and sickle cell disease [90] . Further clinical trials are needed to evaluate these new applications.…”

Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer

“…A phase 1 study (CAM-PLEX study) for assessing the safety of continuous administration of Plerixafor (AMD3100) in patients with advanced pancreatic, ovarian and colon cancer has been completed (NCT 02179970) ( Table 1 ). The results of the phase 1 study demonstrate that continuous administration of Plerixafor induces intratumoral CD8 + and natural killer (NK) cell accumulation in patients with pancreatic and colorectal cancer [ 43 ]. BL-8040 (motixafortide) is a CXCR4 antagonist, and a phase 2 study shows that BL-8040 increases CD8 + T cell tumor infiltration, decreases myeloid-derived suppressor cells and circulating regulatory T cells (COMBAT trial) (NCT02826486) ( Table 1 ) [ 44 ].…”