Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1

• Published in: Frontiers in immunology 2021-02, Vol.12, p.607044
• Main Authors: Renrick, Ariana N, Thounaojam, Menaka C, de Aquino, Maria Teresa P, Chaudhuri, Evan, Pandhare, Jui, Dash, Chandravanu, Shanker, Anil
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Bortezomib - pharmacology; cancer immunotherapy; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cytokines - metabolism; Disease Models, Animal; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; immunomodulators; immunosuppression; Lymphocyte Count; lymphocyte function; Mice; microRNA; MicroRNAs - chemistry; MicroRNAs - genetics; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - chemistry; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - genetics; Proteasome Inhibitors - pharmacology; RNA Folding; RNA Interference; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein - chemistry; Suppressor of Cytokine Signaling 1 Protein - genetics; tumor microenvironment
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.607044

Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor-bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8 T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8 T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib-induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8 T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1 phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155-dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1-mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib-mediated lymphocyte-stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment.