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

Abstract

Cancer immunotherapy shows great promise but many patients fail to show objective responses, including in cancers that can respond well such as melanoma and renal adenocarcinoma. The proteasome inhibitor bortezomib sensitizes solid tumors to apoptosis in response to TNF-family death ligands. Since T cells provide multiple death ligands at the tumor site, we investigated the effects of bortezomib on T cell responses in immunotherapy models involving low-avidity antigens. Bortezomib did not affect lymphocyte or tissue-resident CD11c+CD8+ dendritic cell counts in tumor-bearing mice, did not inhibit dendritic cell expression of co-stimulatory molecules and did not decrease MHC class I/II-associated antigen presentation to cognate T cells. Rather, bortezomib activated NF-κB p65 in CD8+ T cells, stabilizing expression of T cell receptor CD3ζ and IL-2 receptor-α, while maintaining IFN-γ secretion to improve FasL-mediated tumor lysis. Notably, bortezomib increased tumor cell surface expression of Fas in mice as well as human melanoma tissue from a responsive patient. In renal tumor-bearing immunodeficient Rag2−/− mice, bortezomib treatment after adoptive T cell immunotherapy reduced lung metastases and enhanced host survival. Our findings highlight the potential of proteasome inhibitors to enhance antitumor T cell function in the context of cancer immunotherapy.

Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction

“…In fact, there are many co-stimulatory and co-inhibitory molecules, and these molecules have been investigated as new therapeutic targets. 31, 32 Therefore, it is difficult to abolish the effects of co-stimulatory signals in vivo completely. There were 2 important studies about antigen presentation after MI.…”

Update on the Current Revolution in Cancer Immunotherapy

“…The NK cells in the proximity of activated CD8 + T cells showed functional remodeling exhibited by upregulation of effector, tissue-migratory and signaling molecules. This work suggests that tapping innate and adaptive lymphocyte teamwork in conjunction with lymphocyte-stimulatory pharmacological strategies, such as bortezomib [18] or engineered Notch ligand multivalent clusters [19], would be key to successful immunotherapy.…”

Notching tumor: Signaling through Notch receptors improves antitumor T cell immunity

“…1). 2,3 Although the molecular mechanisms underlying these effects need to be dissected, these studies highlight the clinical relevance of augmenting noncanonical downstream Notch signaling pathways by pharmacological agents such as DLL1 clusters or bortezomib in adoptive T cell immunotherapies.…”

“…Three recent studies show that it is possible to restore the cross-regulatory loops of Notch-NF-kB signaling in lymphoid cells of tumor-bearing hosts by Deltalike Notch ligand-1 (DLL1) 1 and proteasome inhibitor bortezomib. 2,3 Such pharmacological manipulations of host immunity enhanced antitumor T cell responses that could improve the outcome of adoptive cell therapy and avoid resistance of cancer cells to chemotherapeutic agents such as tyrosine kinase inhibitors (TKIs).…”