期刊
MELANOMA RESEARCH
卷 30, 期 1, 页码 14-25出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CMR.0000000000000639
关键词
checkpoint inhibitors; CXCR4 inhibition; immunotherapy; melanoma; myeloid-derived suppressor cells; renal cell carcinoma; regulatory T cells
资金
- X4 Pharmaceuticals, Cambridge, MA, USA
- NIH [5P50CA101942]
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 (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.
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