Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity.
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. Because 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 costimulatory 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 IL2 receptor-α, while maintaining IFNγ 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.
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee. Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. School of Graduate Studies and Research, Meharry Medical College, Nashville, Tennessee. ashanker@mmc.edu sayerst@mail.nih.gov.
Anil
A
Shanker
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee. School of Graduate Studies and Research, Meharry Medical College, Nashville, Tennessee. Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, Nashville, Tennessee.
Samuel T
ST
Pellom
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee.
Duafalia F
DF
Dudimah
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee.
Menaka C
MC
Thounaojam
Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland.
Rachel L
RL
de Kluyver
Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland. Basic Sciences Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
Alan D
AD
Brooks
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Hideo
H
Yagita
Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland.
Daniel W
DW
McVicar
Division of Hematology/Oncology, Departments of Dermatology and Internal Medicine, University of California School of Medicine, Davis, California.
William J
WJ
Murphy
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
Dan L
DL
Longo
Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland. Basic Sciences Program, Leidos Biomedical Research, Inc., Frederick, Maryland. ashanker@mmc.edu sayerst@mail.nih.gov.
Thomas J
TJ
Sayers
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000069286:Bortezomib / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000637:transplantation*
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D000069286:Bortezomib