Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Cancer immunotherapy shows promise but faces challenges with patient response rates, particularly in solid tumors.
• Proteasome inhibitors, such as bortezomib, are known to sensitize solid tumors to apoptosis induced by TNF-family death ligands.

Purpose of the Study:

• To investigate the effects of bortezomib on T-cell responses in cancer immunotherapy models, especially those involving low-avidity antigens.
• To determine if bortezomib enhances anti-tumor T-cell function and improves treatment outcomes.

Main Methods:

• Utilized tumor-bearing mouse models and immunodeficient Rag2(-/-) mice.
• Administered bortezomib and assessed T-cell activation markers (NF-κB p65, CD3ζ, IL2 receptor-α), cytokine secretion (IFNγ), and tumor cell apoptosis (FasL-mediated lysis).
• Evaluated effects on dendritic cell counts, costimulatory molecule expression, and antigen presentation.

Main Results:

• Bortezomib activated NF-κB p65 in CD8(+) T cells, stabilizing key T-cell receptors and maintaining IFNγ secretion.
• Treatment increased tumor cell surface expression of Fas, enhancing FasL-mediated tumor cell lysis.
• In renal cancer models, bortezomib reduced lung metastases and improved host survival following adoptive T-cell immunotherapy.

Conclusions:

• Bortezomib enhances anti-tumor T-cell function and tumor cell susceptibility to T-cell-mediated killing.
• Proteasome inhibitors represent a potential strategy to improve the efficacy of cancer immunotherapy.