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

Pellom ST, Dudimah DF, Thounaojam MC, Uzhachenko RV, Singhal A, Richmond A, Shanker A
Oncotarget. 2017 8 (5): 8604-8621

PMID: 28052005 · PMCID: PMC5352426 · DOI:10.18632/oncotarget.14365

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.

MeSH Terms (24)

Adenocarcinoma Animals Antineoplastic Agents Bortezomib Breast Neoplasms CD8-Positive T-Lymphocytes Cell Line, Tumor Cytokines Female Fibrosarcoma Kidney Neoplasms Lung Neoplasms Lymphocytes, Tumor-Infiltrating Mice, Inbred BALB C Mice, Transgenic Phosphatidylinositol 3-Kinase Proteasome Endopeptidase Complex Proteasome Inhibitors Proto-Oncogene Proteins c-akt Receptors, Cytokine Signal Transduction STAT5 Transcription Factor Tumor Escape Tumor Microenvironment

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