Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy

By S. Highfill, Yongzhi Cui, Amber J. Giles, Jillian P. Smith, Hua Zhang, Elizabeth Morse, R. Kaplan, C. Mackall. Science Translational Medicine, 2014

705 citations recorded by the source corpus.

Preventing trafficking of myeloid-derived suppressor cells to the tumor site enhances the efficiency of checkpoint blockade. Cross-Checking Cancer Immunological checkpoint blockades are a promising approach in cancer immunotherapy—pushing the immune response to the tumor past tolerance into attack mode. Now, Highfill et al. show that inhibiting myeloid-derived suppressor cells by preventing their trafficking into the tumor site can enhance the efficiency of checkpoint blockade. They found in a mouse model of rhabdomyosarcoma that blocking a chemokine receptor on myeloid-derived suppressor cells in conjunction with antibodies to the checkpoint molecule programmed death 1 induced substantial antitumor effects. Moreover, patients with rhabdomyosarcoma that had elevated levels of ligands for this chemokine receptor had poorer prognosis. These data suggest that combining these therapies may increase the likelihood of patient response, checking cancer into the boards. 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+Ly6Ghi MDSCs, and CXCR2 deficiency prevented CD11b+Ly6Ghi 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+Ly6Ghi 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+Ly6Ghi 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/915ef806c95550a75567de0317338661bb4e5185

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In Immunology

1. K. Flaherty
2. D. Barbie
3. Russell W. Jenkins
4. D. Gabrilovich
5. V. Bronte
6. J. Massagué
7. E. Batlle

In Oncology

1. K. Flaherty
2. D. Barbie
3. Russell W. Jenkins
4. D. Gabrilovich

Citations in the corpus

• CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, neutral): “CXCR2 also regulates the migration of myeloid-derived suppressor cells (MDSCs) (Highfill et al., 2014).”
• Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “Depletion of these immune suppressive cell types (e.g., MDSCs and Tregs) has experimentally been shown to enhance anti-tumour immune responses overcoming innate resistance (Highfill et al, 2014; Ngiow et al, 2015).”
• Myeloid-derived suppressor cells (2017, background): “The level of MDSCs is associated with patient responses to CTLA-4/ipilimumab (58, 59) and PD-1 (60, 61) inhibition.”
• Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases (2017, neutral): “Inhibition of programmed death-1 (PD-1) by anti-PD-1 antibody prevented tumor growth during early phase tumor progression, but delayed treatment with anti-PD-1 therapy showed little benefits [346].”
• Immune escape mechanisms as a guide for cancer immunotherapy (2014, background): “In support of this approach, Highfill and colleagues recently demonstrated a role for inhibiting the trafficking of myeloid suppressor cells into tumors by disruption of CXCR2 signaling as a strategy for unveiling the antitumor activity of anti–PD-1 therapy (34).”