SDF-1/CXCR4 axis facilitates myeloid-derived suppressor cells accumulation in osteosarcoma microenvironment and blunts the response to anti-PD-1 therapy.

Immune checkpoint inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. To date, PD-1/PD-L1 inhibitors have been approved for the treatment of specific types of tumors and obtained good clinical efficacy. However, patients with osteosarcoma showed poor response to anti-PD-1/PD-L1 therapy, the mechanism of which is not well understood. In this study, we found that osteosarcoma tissues were heavily infiltrated by myeloid-derived suppressor cells (MDSCs) which could inhibit cytotoxicity T cell (CTL) expansion. Further study revealed that the vast majority of tumor-infiltrating MDSCs were CXCR4 positive and could migrate toward an SDF-1 gradient. The binding of SDF-1 to its receptor CXCR4 results in the activation of downstream AKT pathway that mediates reduced apoptosis of MDSCs. We also demonstrated that AMD3100, a CXCR4 antagonist, has a synergistic effect with anti-PD-1 antibody in tumor treatment in a murine model of osteosarcoma. These findings provide the basis for establishing CXCR4 antagonist and PD-1/PD-L1 inhibitors co-administration as a novel therapeutic regimen for patients with osteosarcoma and hold great promise for improving the therapeutic effect of osteosarcoma.

Jiang K ，Li J ，Zhang J ，Wang L ，Zhang Q ，Ge J ，Guo Y ，Wang B ，Huang Y ，Yang T ，Hao D ，Shan L ... -  《-》

Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.

Zeng Y ，Li B ，Liang Y ，Reeves PM ，Qu X ，Ran C ，Liu Q ，Callahan MV ，Sluder AE ，Gelfand JA ，Chen H ，Poznansky MC ... -  《-》

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.

Wu A ，Maxwell R ，Xia Y ，Cardarelli P ，Oyasu M ，Belcaid Z ，Kim E ，Hung A ，Luksik AS ，Garzon-Muvdi T ，Jackson CM ，Mathios D ，Theodros D ，Cogswell J ，Brem H ，Pardoll DM ，Lim M ... -  《-》

Enhanced Anti-Leukemic Effects through Induction of Immunomodulating Microenvironment by Blocking CXCR4 and PD-L1 in an AML Mouse Model.

Hwang HS ，Han AR ，Lee JY ，Park GS ，Min WS ，Kim HJ ... -  《-》

GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma.

Park JA ，Cheung NV 《Journal of Hematology & Oncology》