期刊
MOLECULAR ONCOLOGY
卷 -, 期 -, 页码 -出版社
WILEY
DOI: 10.1002/1878-0261.13541
关键词
CDK4/6 inhibitors; DNA-damaging agents; SASP; therapy-induced senescence; tumor microenvironment
类别
This study compared the senescence induced by cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with that induced by conventional DNA-damaging agents. The results showed that both types of agents caused a similar degree of senescence, but DNA-damaging agents increased the expression of senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity and angiogenesis. CDK4/6i-induced senescent cells maintained the expression of anti-tumor immunomodulatory proteins at a similar or higher intensity compared to cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-kappa B) and p53 activation.
Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGF beta, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-kappa B) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.
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