Journal
IMMUNITY INFLAMMATION AND DISEASE
Volume 8, Issue 4, Pages 672-683Publisher
WILEY
DOI: 10.1002/iid3.356
Keywords
DLBCL; immunosuppressive cells; SASP; SENEX gene; stress-induced premature senescence
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Funding
- Research Fund Project of Anhui Medical University [2018xkj026]
- National Natural Science Foundation of China [81670179]
- National Natural Science Foundation Incubation Project of the Second Hospital of Anhui Medical University [2019GQFY11]
- Provincial Natural Science Research Key Project of Anhui Higher Education Institutions [KJ2019A0254]
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Background: The underlying cause of relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is usually related to apoptosis resistance to antitumor drugs. The recent years have provided lots of evidence that tumor cells may undergo stress-induced premature senescence (SIPS) in response to chemotherapy, but how SIPS affects lymphoma cells remains inconclusive. Methods: Fifty-two DLBCL patients, including 6 newly diagnosed (ND), 17 complete remissions (CR), and 29 (r/r), were enrolled in this study. We used a senescence-associated-beta-galactosidase (SA-beta-Gal) staining kit for senescence staining. Suppressive immune cells including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were detected by flow cytometry (FCM). Secreted cytokines were measured by ELISA Kit andSENEXgene expression was detected by a quantitative real-time polymerase chain reaction. We used 40 nM doxorubicin to induce the SIPS model of DLBCL in vitro. Apoptosis and proliferation activity of senescent LY8 cells were respectively detected by FCM and CCK8.SENEXgene was silenced by RNA interference. Results: The proportion of senescent lymphoma cells was significantly increased in r/r DLBCL patients, concomitant with increased Treg, MDSC, and various secreted cytokines with proinflammatory and immunosuppressive effects. The SENEXgene was significantly elevated in the SIPS model. Senescent DLBCL cells had good antiapoptotic ability and proliferative activity accompanied by increased immunosuppressive cytokines. Interestingly, when we silenced the SENEXgene in the DLBCL cell line, the results were the opposite to the above. Conclusion: SIPS activated by the SENEXgene mediates apoptosis resistance of r/r DLBCL via promoting immunosuppressive cells and cytokines.
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