Related Experiment Video
Updated: Apr 29, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy
Steven L Highfill1, Yongzhi Cui1, Amber J Giles1
1Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.
Insights
Targeting myeloid-derived suppressor cells (MDSCs) trafficking to tumors can improve cancer immunotherapy. Inhibiting CXCR2 prevents MDSC accumulation, enhancing anti-programmed death 1 (PD1) therapy effectiveness against pediatric sarcomas.
Area of Science:
- Immunology
- Oncology
- Pediatric Cancer Research
Background:
- Cancer progression is driven by immune suppression, with programmed death 1 (PD1) signaling and myeloid-derived suppressor cells (MDSCs) being key mechanisms of immune escape.
- Rhabdomyosarcoma (RMS), a common childhood sarcoma, utilizes these pathways for tumor immune evasion.
Purpose of the Study:
- To investigate targeting PD1 and MDSC pathways in pediatric rhabdomyosarcoma.
- To determine the role of CXCR2 in MDSC recruitment and its impact on anti-PD1 therapy efficacy.
Main Methods:
- Assessed PD-L1 expression and anti-PD1 efficacy in murine RMS models.
- Investigated the role of CXCR2 in MDSC trafficking using CXCR2-deficient mice and anti-CXCR2 monoclonal antibodies.
- Analyzed CXCR2 ligand production in human pediatric sarcomas and correlated CXCL8 levels with patient survival.
Main Results:
- Early anti-PD1 treatment was effective in murine RMS, but delayed treatment showed limited benefit.
- RMS induced expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, which are crucial for local immunosuppression.
- Inhibiting MDSC trafficking via CXCR2 deficiency or anti-CXCR2 therapy restored the efficacy of delayed anti-PD1 treatment.
- Human pediatric sarcomas express CXCR2 ligands, with elevated CXCL8 associated with poorer survival.
Conclusions:
- Accumulation of MDSCs in the tumor microenvironment limits the effectiveness of cancer checkpoint blockade therapies.
- CXCR2 is a viable therapeutic target for modulating tumor immune escape.
- CXCR2(+)CD11b(+)Ly6G(hi) MDSCs represent a significant suppressive myeloid subset in pediatric sarcomas, and targeting their trafficking offers a strategy to enhance immunotherapy outcomes.
