拮抗β-Catenin/BCL9相互作用可抑制多形核髓源性抑制细胞的生成与维持

Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of myeloid-lineage cells thought to play a role in the immunosuppressive cancer environment. Evidence indicates that in colorectal cancer (CRC) patients, MDSCs accumulate in peripheral blood (PB), secondary lymphoid organs and tumors. Further, nonclinical models have proved their contribution in suppressing anti-tumor T-cell responses. Thus, MDSCs have become an attractive target of therapeutic strategies aimed at reversing tumor-related immunosuppression and, as these cells can be readily assessed in PB fractions, as a pharmacodynamic biomarker to track therapeutic response and disease progression. Despite the great interest in MDSC biology, the genetic pathways responsible for their expansion and maintenance are poorly understood, in part due to the difficulty in defining MDSCs immunophenotype. ST316 is a clinical-stage peptide antagonist of the beta-catenin/BCL9 protein complex that is currently being evaluated in a Phase 1/2 study (NCT05848739) in patients with advanced CRC. Consistent with literature, polymorphonuclear (PMN)-MDSCs were elevated in the PB of most evaluable patients in the Phase 1 part of the study (7 of 8 patients); strikingly, ST316 exposure resulted in statistically significant suppression of MDSCs in the PB of all patients who displayed baseline elevations (7 of 7 evaluated). Similar increases in PMN-MDSCs were observed at baseline in the immunocompetent APC min and CT-26 CRC murine models, while exposure to ST316 resulted in dose-dependent decreases in their frequency. Mechanistically, ST316 prevented proliferation of immature MDSC precursor populations in the bone marrow while accelerating mature MDSC turnover in PB and splenic fractions. Transcriptomics analysis indicated that ST316 suppressed Wnt/beta-catenin signatures in PMN-MDSCs. In addition, ST316 reduced expression of several myeloid markers associated with neutrophil differentiation, including CD101, CD300a, and Siglec-F, suggesting that these markers reflect beta-catenin/BCL9 controlled dynamics of MDSCs generation. Overall, our results identify a new role for beta-catenin/BCL9 signaling in MDSC generation and maintenance, and identify suppression of MDSCs as a consequence of ST316 exposure in nonclinical and clinical tumor settings.