CXCR4 Mediates Immune-Privilege in T Cell-Excluded Tumors Douglas T Fearon1,2,3, Martin Smoragiewicz2, James Thaventhiran2, Daniele Biasci2, Lukasz Magiera2, Bristi Basu2, Duncan Jodrell2. 1Cold Spring Harbor Laboratory; 2University of Cambridge; 3Weill Cornell Medicine
The inability of cancer-specific T cells to accumulate in most epithelial tumors causes cancers to escape immune control by T cell checkpoint antagonists. In 2013, we reported that conditional, selective depletion of cancer-associated fibroblasts (CAFs) from the KPC autochthonous mouse model of pancreatic ductal adenocarcinoma (PDA) slowed tumor growth in a T cell-dependent manner, and made the tumor sensitive to inhibition of the PD-1/PD-L1 checkpoint (Feig C, et al. PNAS 2013). Analysis of these tumors showed that only CAFs and endothelial cells expressed the chemokine, Cxcl12, which was informative because previous work by others had shown that signaling via Cxcr4, the receptor for Cxcl12, prevented the accumulation of T cells in the virally-infected brain parenchyma of mice (McCandless EE, et al. PNAS 2008). Therefore, we administered the CXCR4 inhibitor, AMD3100/Plerixafor, and anti-PD-L1 to mice with PDA. T cells rapidly accumulated in the tumors, and killed almost all cancer cells in one week. On the basis of these results, we initiated a phase 1 trial of continuous administration of AMD3100 for 7 days to colorectal and PDA patients, and assessed the therapy-induced changes in the transcriptomes of core biopsies of metastases obtained before and at the end of therapy. Despite the short duration of CXCR4 inhibition as monotherapy, we found increases in the expression of immune genes that were comparable to those caused by successful treatment of melanoma with anti-PD-1 or anti-CTLA-4. Furthermore, these increases correlated with decreased expression of genes characteristic of replicating cancer cells. Thus, CXCR4 signaling establishes immune privilege in human cancer.
Credits: None available.
You must be logged in and own this product in order to