Original Articles: Basic ScienceCXCR4 inhibition modulates the tumor microenvironment and retards the growth of B16-OVA melanoma and Renca tumorsSaxena, Ruchia; Wang, Yanb; Mier, James W.aAuthor Information aBeth Israel Deaconess Medical Center, Boston bX4 Pharmaceuticals, Cambridge, Massachusetts, USA Received 17 January 2019 Accepted 15 July 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.melanomaresearch.com. Correspondence to James W. Mier, MD, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA, Tel: +1 617 975 7505; fax: +1 617 667 0230; e-mail: [email protected] Melanoma Research: February 2020 - Volume 30 - Issue 1 - p 14-25 doi: 10.1097/CMR.0000000000000639 Buy SDC Metrics Abstract To determine whether blockade of the chemokine receptor CXCR4 might alter the tumor microenvironment and inhibit tumor growth, we tested the efficacy of the CXCR4 antagonist X4-136 as a single agent and in combination with various immune checkpoint inhibitors in the syngeneic murine melanoma model B16-OVA. We also tested its activity alone and in combination with axitinib in the renal cancer model Renca. We found that X4-136 exhibited potent single agent antitumor activity in the B16-OVA model that was additive to that of an anti-PDL1 antibody. The antitumor activities were associated with a reduction in the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells and an increase in the number of tumor-specific CD8+/perforin+ cells in the tumor-microenvironment. Apart from these immune effects, X4-136 alone and in combination with checkpoint inhibitors inhibited the Akt/FOXO-3a cell survival pathway in vitro and in vivo, suggesting that it might have antitumor activity independent of its effects on immune cell trafficking. Similar effects on tumor growth and cytotoxic T lymphocytes infiltration were observed in the Renca model. These studies show that the effects of CXCR4 blockade on immune cell trafficking might serve as a useful adjunct to immune checkpoint inhibitors and other therapies in the treatment of cancer. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.