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

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 7

SX-682 treatment effect is not due to direct alteration of tumor cell viability, invasive capacity, or immunogenicity.

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SX-682 treatment effect is not due to direct alteration of tumor cell vi...
(A) MOC1 or LLC cells were assessed for CXCR1 or CXCR2 expression by flow cytometry, compared to fibroblasts, endothelial, immune or epithelial cells from MOC1 or LLC tumors in vivo. Live CD45.2–CD31–PDGFR– oral mucosal epithelial cells and lung epithelial cells were used as comparators for MOC1 and LLC, respectively. (B) CXCR1 and CXCR2 expression on day 25 CD45.2–CD31–PDGFR– MOC1 or LLC tumor cells following SX-682 treatment beginning on day 10 or 20 after tumor implantation was assessed by flow cytometry. (C) MOC1 or LLC cells were plated in increasing doses of SX-682 and evaluated for alteration in viability via impedance analysis. (D) MOC1 or LLC cells were exposed to SX-682 (1 μM for 24 hours) and assessed for induction of apoptosis via flow cytometry. (E) Extracellular matrix invasion of MOC1 or LLC cells was assessed using 10% FBS (positive control) or CXCL1 (50 ng/ml) as the chemoattractant in the presence or absence of SX-682 (1 μM). (F) MOC1 or LLC cells expressing SIINFEKL were exposed to activated OT-I T cells in the presence or absence of SX-682 (cells plated in 1 μM) and T cell killing was assessed via impedance analysis. Representative impedance plots on the left, with quantification at 8 hours on the right. Representative data from 1 of at least 2 independent assays with similar results shown. *P < 0.05; ***P < 0.001 by Student’s t test.