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Oncotarget. 2017 Jan 31;8(5):8604-8621. doi: 10.18632/oncotarget.14365.

Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function.

Author information

1
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee, USA.
2
Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, Nashville, Tennessee, USA.
3
School of Graduate Studies and Research, Meharry Medical College, Nashville, Tennessee, USA.
4
Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
5
Department of Veterans Affairs, Nashville, Tennessee, USA.
6
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
7
Host-Tumor Interactions Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
8
Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA.
9
Vanderbilt Center for Translational and Clinical Immunology, Vanderbilt University, Nashville, Tennessee, USA.

Abstract

Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.

KEYWORDS:

CD8+ T cells; adoptive cell therapy; cancer immunotherapy; immunosuppression; proteasome inhibition

PMID:
28052005
PMCID:
PMC5352426
DOI:
10.18632/oncotarget.14365
[Indexed for MEDLINE]
Free PMC Article

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