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Updated: Jan 20, 2026
Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
SDF-1/CXCR4 axis facilitates myeloid-derived suppressor cells accumulation in osteosarcoma microenvironment and
Kuo Jiang1, Jia Li2, Jitao Zhang1
1Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China.
Abstract:
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.
Insights
Osteosarcoma resists PD-1/PD-L1 therapy due to myeloid-derived suppressor cells (MDSCs). Targeting the CXCR4 pathway with antagonists alongside PD-1 inhibitors shows promise for improved osteosarcoma treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs), like anti-PD-1/PD-L1, modulate immune cell-tumor interactions for cancer suppression.
- While effective for many cancers, osteosarcoma patients exhibit limited response to PD-1/PD-L1 therapy, with underlying mechanisms unclear.
Purpose of the Study:
- Investigate the mechanisms behind osteosarcoma's poor response to anti-PD-1/PD-L1 therapy.
- Identify potential therapeutic strategies to enhance treatment efficacy in osteosarcoma.
Main Methods:
- Analyzed osteosarcoma tissue for immune cell infiltration, specifically myeloid-derived suppressor cells (MDSCs).
- Investigated the role of CXCR4 and its ligand SDF-1 in MDSC function and survival.
- Evaluated the combination of a CXCR4 antagonist (AMD3100) and anti-PD-1 antibody in a murine osteosarcoma model.
Main Results:
- Osteosarcoma tissues showed significant infiltration of myeloid-derived suppressor cells (MDSCs) that suppressed cytotoxic T cell (CTL) expansion.
- Tumor-infiltrating MDSCs were predominantly CXCR4 positive and migrated towards SDF-1 gradients.
- SDF-1/CXCR4 signaling activated the AKT pathway, reducing MDSC apoptosis.
- AMD3100 combined with anti-PD-1 antibody demonstrated synergistic anti-tumor effects in vivo.
Conclusions:
- MDSCs, via the SDF-1/CXCR4 axis, contribute to immune evasion in osteosarcoma.
- Combining CXCR4 antagonists with PD-1/PD-L1 inhibitors represents a promising therapeutic strategy for osteosarcoma.
- This combination therapy holds potential for improving clinical outcomes in osteosarcoma patients.
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