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Chimeric exosomes-derived immunomodulator restoring lymph node microenvironment for sensitizing TNBC immunotherapy

ABSTRACT: Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), whereas is effective in a portion of patients. Our clinical studies found that lipid homeostasis imbalance and dendritic cells (DCs) dysfunction contributed to the immunosuppressive microenvironment in the lymph nodes (LNs) of TNBC patients following immunotherapy, which greatly affected the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator, EMV@SS-Toy, involving a polysulfide bond-bridged mesoporous silica nanoparticles (SS-MSN) as a reactive oxygen species (ROS) scavenger and responsive carrier nucleus, loading with the (IRE1α-XBP1) inhibitor toyocamycin (Toy) and coating with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing via homologous targeting and chemokine-guided navigation, enabling a pathological ROS-responsive drug release, dual-stress pathway regulation, thereby restoring and DCs’ function and LNs’ immune microenvironment. As expected, the immunomodulator markedly boosted the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases and establishing long-term immune surveillance. Our study provides potent directions for translational immunotherapy through optimizing the LNs’ microenvironment in TNBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE270025 | GEO | 2024/10/01

REPOSITORIES: GEO

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Project description:Triple-negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor α (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy, recently supplemented by immunotherapy [37296893]. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including gamma secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. We confirmed that SS, a known gamma secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, the anti-tumor effects of SS were significantly enhanced when combined with α-PD1 immunotherapy in our TNBC organoids and in vivo. Our data support further investigation of SS for the treatment of TNBC, in conjunction with standard of care chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option solution for a patient population in need of effective therapies.

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Chimeric exosomes-derived immunomodulator restoring lymph node microenvironment for sensitizing TNBC immunotherapy

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