CDK4/6 inhibitors induce breast cancer senescence with enhanced anti‐tumor immunogenic properties compared with DNA‐damaging agents

Abstract

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, TGFβ, 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‐κB) 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.

Keywords

• CDK4/6 inhibitors
• DNA‐damaging agents
• SASP
• therapy‐induced senescence
• tumor microenvironment