Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

Specifically, VEGF increased blood vessel density, whereas the proinflammatory SASP (IL-6, CCL5, and CXCL1) promoted endothelial cell activation, increasing vessel permeability, leading to improved access of gemcitabine and facilitated tumor infiltration by CD8+ T cells, promoting tumor destruction.

“Specifically, VEGF increased blood vessel density, whereas the proinflammatory SASP, namely, IL-6, CCL5, and CXCL1, promoted endothelial cell activation, increasing vessel permeability. This led to improved access of the chemotherapeutic drug gemcitabine and facilitated tumor infiltration by CD8+ T cells, promoting tumor destruction (Ruscetti et al. 2020).”

In PDAC, treatment with T/P led to SASP-facilitated remodeling of the tumor microenvironment, which exposed therapeutic vulnerabilities.

“In PDAC, treatment with T/P led to SASP-facilitated remodeling of the tumor microenvironment (TME), which exposed therapeutic vulnerabilities.”

Combining either gemcitabine or anti-PD-1 therapy with T/P produces a potent antitumor effect.

“In this way, combining either gemcitabine or anti-PD-1 therapy with T/P produces a potent antitumor effect.”

Dual inhibition of MEK and CDK4/6 also led to senescence phenotypes in a mouse model of Kras-mutant pancreatic ductal adenocarcinoma (PDAC).

“Dual inhibition of MEK and CDK4/6 also led to senescence phenotypes in a mouse model of Kras -mutant pancreatic ductal adenocarcinoma (PDAC) 152 .”

SASP factors secreted by the senescent PDAC cells contributed to vascular remodelling, which facilitated drug delivery and promoted the accumulation of CD8+ T cells whose cytotoxicity could be enhanced through antibody-mediated inhibition of PD-1.

“Importantly, SASP factors secreted by the senescent PDAC cells contributed to vascular remodelling, which facilitated drug delivery and promoted the accumulation of CD8 + Tcells whose cytotoxicity could be enhanced through antibody- mediated inhibition of PD-1 (ref. 152 ) .”

Dual inhibition of MEK and CDK4/6 induced senescence in a mouse model of Kras-mutant PDAC, favoured tumour vascularization and endothelial cell activation, and enhanced the efficacy of anti-PD-1 antibodies.

“For example, dual inhibition of MEK and CDK4/6 induced senescence in a mouse model of Kras - mutant PDAC, favoured tumour vascularization and endothelial cell activation, and ultimately enhanced the efficacy of anti- PD-1 antibodies in this model 152 .”

In a preclinical mouse model of pancreatic ductal adenocarcinoma, T/P drugs induced senescence of pancreatic cancer cells and activated SASP-dependent vascular remodeling, which enhances the uptake and efficacy of chemotherapy drugs and promotes the infiltration of T cells into tumor tissues.

“In a preclinical mouse model of pancreatic ductal adenocarcinoma, T/P drugs induced senescence of pancreatic cancer cells and activated SASP-dependent vascular remodeling, which not only enhances the uptake and efficacy of chemotherapy drugs but also promotes the infiltration of T cells into tumor tissues [78].”

The SASP induced by chemotherapy increases the sensitivity of PD-1 and chemotherapy, thereby reducing tumor progression and metastasis.

“For example, the SASP induced by chemotherapy increases the sensitivity of PD-1 and chemotherapy, thereby reducing tumor progression and metastasis [78].”

In preclinical KRAS-driven lung and pancreatic adenocarcinoma models, trametinib and palbociclib synergize to induce a SASP-dependent vascular response that allows immune effector cells to infiltrate tumors.

“trametinib synergizes with palbociclib at inducing a SASP-dependent vascular response that enables tumor infiltration by immune effector cells”