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Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy
Lillian Sun, … , John Zebala, Clint T. Allen
Lillian Sun, … , John Zebala, Clint T. Allen
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e126853. https://doi.org/10.1172/jci.insight.126853.
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Research Article Oncology

Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy

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Abstract

Recruitment of myeloid-derived suppressor cells (MDSCs) into tumors induces local immunosuppression in carcinomas. Here, we assessed whether SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2, could block tumor MDSC recruitment and enhance T cell activation and antitumor immunity following multiple forms of immunotherapy. CXCR2+ neutrophilic MDSCs (PMN-MDSCs) were the most abundant myeloid cell subset within oral and lung syngeneic carcinomas. PMN-MDSCs demonstrated greater suppression of tumor-infiltrating lymphocyte killing of targets compared with macrophages. SX-682 significantly inhibited trafficking of PMN-MDSCs without altering CXCR2 ligand expression. Trafficking of CXCR1+ macrophages was unaltered, possibly due to coexpression of CSF1R. Reduced PMN-MDSC tumor infiltration correlated with enhanced accumulation of endogenous or adoptively transferred T cells. Accordingly, tumor growth inhibition or the rate of established tumor rejection following programed death–axis (PD-axis) immune checkpoint blockade or adoptive cell transfer of engineered T cells was enhanced in combination with SX-682. Despite CXCR1/2 expression on tumor cells, SX-682 appeared to have little direct antitumor effect on these carcinoma models. These data suggest that tumor-infiltrating CXCR2+ PMN-MDSCs may prevent optimal responses following both PD-axis immune checkpoint blockade and adoptive T cell transfer therapy. Abrogation of PMN-MDSC trafficking with SX-682 enhances T cell–based immunotherapeutic efficacy and may be of benefit to patients with MDSC-infiltrated cancers.

Authors

Lillian Sun, Paul E. Clavijo, Yvette Robbins, Priya Patel, Jay Friedman, Sarah Greene, Rita Das, Chris Silvin, Carter Van Waes, Lucas A. Horn, Jeffrey Schlom, Claudia Palena, Dean Maeda, John Zebala, Clint T. Allen

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Figure 1

Tumor-infiltrating CXCR2+Ly6Ghi myeloid cells suppress TIL function to a greater degree than CXCR1+ macrophages.

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Tumor-infiltrating CXCR2+Ly6Ghi myeloid cells suppress TIL function to a...
Day 20 tumors from wild-type (WT) B6 mice bearing MOC1 (A) or LLC (B) tumors were digested and assessed for infiltration of myeloid cells by flow cytometry. Representative dot plots of gating strategy on the left, with pie graphs of myeloid cell constituency on the right. Ly6GhiLy6CintF4/80– myeloid cells or F4/80+ macrophages were sorted from MOC1 (C) or LLC (D) tumors and assessed for ability to suppress TIL (10:1 E/T) killing of parental tumor cells. Ly6GhiLy6CintF4/80– myeloid cells or F4/80+ macrophages were plated at a 3:1 ratio to TILs. Representative impedance plots shown on the left, with quantification of percentage loss of cell index at 12 hours quantified on the right. CXCR1 and CXCR2 expression on MOC1 (E) and LLC (F) tumor-infiltrating immune cells was assessed via flow cytometry. Representative data from 1 of 2 independent assays with similar results shown. MFI, mean fluorescence intensity. *P < 0.05; **P < 0.01; ***P < 0.001 by ANOVA. n/s, nonsignificant.

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