Abstract
Drug-induced pancreatic cancer cell senescence increased vulnerability to chemo- and immunotherapy.
Major Finding: Drug-induced pancreatic cancer cell senescence increased vulnerability to chemo- and immunotherapy.
Mechanism: Senescence caused vascular remodeling, promoting drug uptake and T-cell infiltration and activity.
Impact: Based on these mouse experiments, exploring these drug combinations in patients may be of interest.
Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes immune-mediated destruction of premalignant cells. Ruscetti, Morris, Mezzadra, and colleagues recently discovered that treatment of KRAS-mutant lung or pancreatic cancer cells with RAS pathway–targeted therapies (the MEK inhibitor trametinib plus the CDK4/6 inhibitor palbociclib) triggered cell-cycle exit via a senescence pathway. Based on this finding, they evaluated the effects of senescence induction on the characteristically hypovascular and immunosuppressive tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC). In genetically engineered and organoid-transplant mouse models, treatment with trametinib plus palbociclib (T+P) caused PDAC senescence and led to vascular remodeling. Further experiments revealed that, upon T+P treatment, angiogenic senescence-associated secretory phenotype (SASP) factors, which are secreted by senescent cells and alter the behavior and proliferation of endothelial cells, were primarily derived from senescent tumor cells and promoted vascular remodeling and activation of endothelial cells. Notably, T+P treatment sensitized the previously described mouse PDAC models and two patient-derived xenograft PDAC models to the standard-of-care cytotoxic chemotherapeutic drug gemcitabine, possibly by enhancing drug uptake by causing vascular remodeling. Additionally, this SASP-dependent vascular remodeling increased infiltration of CD8+ T cells into the PDAC TME, but these T cells quickly began exhibiting an exhausted phenotype and did not enhance the antitumor effects of T+P treatment. However, when combined with PD-1 blockade, CD8+ T-cell dysfunction was prevented, enabling these T cells to contribute to an antitumor response. In fact, the efficacy of T+P plus anti–PD-1 far surpassed that of T+P alone, anti–PD-1 alone, or gemcitabine. Thus, senescence-inducing T+P treatment can sensitize PDAC—with its notoriously immunosuppressive TME—to T cell–mediated killing. Together, these results reveal that T+P treatment can cause therapeutically exploitable vulnerabilities in PDAC by promoting senescence-mediated vascular remodeling and T-cell infiltration and activity in the PDAC TME.
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