Stress‐induced premature senescence activated by the SENEX gene mediates apoptosis resistance of diffuse large B‐cell lymphoma via promoting immunosuppressive cells and cytokines

Abstract

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‐β‐galactosidase (SA‐β‐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 and SENEX gene 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. SENEX gene 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 SENEX gene 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 SENEX gene in the DLBCL cell line, the results were the opposite to the above. Conclusion SIPS activated by the SENEX gene mediates apoptosis resistance of r/r DLBCL via promoting immunosuppressive cells and cytokines.

Elevated circulating myeloid‐derived suppressor cells associated with poor prognosis in B‐cell non‐Hodgkin's lymphoma patients

“…32 It is worth noting that our research group previously proposed that senescent lymphoma cells of relapsed and refractory DLBCL patients might be involved in inducing the generation of immunosuppressive cells such as MDSCs and Treg through secreting a variety of immunosuppressive cytokines (known as senescence-associated secretory phenotype, SASP), thereby mediating the resistance of tumor apoptosis. 33 Under the effects of various factors secreted by tumor cells, MDSCs secreted a variety of proproliferative, proinflammatory, and immunosuppressive molecules via activating their own S1PR1-STAT3, TGF-β, and other signaling pathways, to make local blood vessels hyperpermeable, to build pre-metastatic microenvironments, to promote the recruitment, seeding, and expansion of tumor cells, and to provide conditions for the formation of metastases. 34,35 Based on the complex and close-knit interaction between MDSCs and tumors, we further explored the relationship between their presence and prognosis in B-NHL patients.…”

Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

“…Moreover, the senescent state is accompanied by distinct phenotypic alterations, including the implementation of the senescence-associated secretory phenotype (SASP), which refers to the production of a complex mixture of secreted soluble and insoluble factors that can induce both beneficial as well as patho-physiological effects [31,[35][36][37][38][39]. Intriguingly, the expression protein profile in MB cells reveals that stem cell-like cells already prior to treatment express a well-known pro-survival and pro-inflammatory cytokine interleukin (IL)-6 (Figure 3c), which is one of the most common SASP factors [40]. Hence, the presence of IL-6 in untreated cells could prime the cells for SASP and allow this phenotype to better spread through the cell population.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Senescence and the associated SASP can affect cells within the tumor microenvironment (TME). The SASP was shown to promote tumorigenesis [ 66 ], EMT [ 67 , 68 , 69 ], cancer stemness [ 70 , 71 ], anticancer drug resistance [ 72 , 73 , 74 ], angiogenesis [ 75 , 76 , 77 , 78 ], immune suppression to promote tumorigenesis [ 79 , 80 ], and tumor suppression by the immune clearance of senescent cells [ 81 ]. Figure 4 shows the roles of the SASP, including tumor suppression and tumor promotion.…”

“…This implies that HDACs can regulate the immune evasion of cancer cells. Since the SASP regulates immune evasion [ 79 ], it is probable that HDACs may regulate senescence. Histone methylation (H3K27me3) in the promoter region of cell-cycle-dependent kinase N2a (CDKN2a) by enhancer of zeste homolog 2 (Ezh2), a histone methyl transferase, inhibited replicative senescence in atrial fibroblasts [ 138 ].…”