Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy.

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Myeloid-derived suppressor cells (MDSCs) promote tumor immunosuppression by infiltrating carcinomas.
• Neutrophilic MDSCs (PMN-MDSCs) expressing CXCR2 are a major suppressive myeloid subset in oral and lung tumors.
• PMN-MDSCs exhibit greater immunosuppressive activity than macrophages in the tumor microenvironment.

Purpose of the Study:

• To evaluate SX-682, a CXCR1/CXCR2 inhibitor, for its ability to block MDSC recruitment.
• To assess if SX-682 enhances T cell activation and antitumor immunity in combination with immunotherapy.
• To determine the therapeutic potential of inhibiting PMN-MDSC trafficking in cancer models.

Main Methods:

• Utilized syngeneic oral and lung carcinoma models in mice.
• Administered SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2.
• Assessed MDSC (specifically PMN-MDSCs) and T cell infiltration using flow cytometry.
• Evaluated the efficacy of SX-682 in combination with PD-axis immune checkpoint blockade and adoptive T cell transfer.

Main Results:

• SX-682 effectively inhibited the trafficking of CXCR2+ PMN-MDSCs into tumors without affecting CXCR2 ligand expression.
• Reduced PMN-MDSC infiltration correlated with increased accumulation of T cells (endogenous and adoptively transferred).
• Combination therapy with SX-682 significantly enhanced tumor growth inhibition and rejection rates in response to PD-axis blockade and adoptive T cell transfer.

Conclusions:

• Tumor-infiltrating CXCR2+ PMN-MDSCs impede optimal responses to PD-axis immune checkpoint blockade and adoptive T cell transfer.
• Abrogating PMN-MDSC trafficking with SX-682 boosts T cell-mediated immunotherapeutic efficacy.
• SX-682 holds potential therapeutic benefit for patients with cancers infiltrated by MDSCs.