Abstract PR01: Senescence induction triggers vascular remodeling and new vulnerabilities to chemo- and immunotherapy in pancreas cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-12, Vol.79 (24_Supplement), p.PR01-PR01
• Main Authors: Ruscetti, Marcus, Morris, John P., Mezzadra, Riccardo, Russell, James, Leibold, Josef, Romesser, Paul B., Simon, Janelle, Kulick, Amanda, Ho, Yu-jui, Fennell, Myles, Li, Jinyang, Norgard, Robert J., Wilkinson, John E., Alonso-Curbelo, Direna, Sridharan, Ramya, Li, Xiang, Heller, Daniel, Stanchina, Elisa de, Stanger, Ben Z., Sherr, Charles J., Lowe, Scott W.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA19-PR01

Background: KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, poor drug delivery, immunosuppression, and de novo resistance to chemo- and immunotherapies. Recently, we demonstrated that a combination of MEK and CDK4/6 inhibitors can potently suppress PDAC tumor cell proliferation through induction of RB-mediated senescence and trigger a senescence-associated secretory phenotype (SASP) capable of remodeling the tumor microenvironment (TME) (Ruscetti et al., Science 2018). Here, we set out to explore how senescence induction could remodel the PDAC TME and alter the treatment landscape of this disease. Methods: The Pdx1-Cre;LSL-KRASG12D;Trp53fl/wt (KPC) genetically engineered mouse model (GEMM) of PDAC, as well as immunocompetent C57BL/6 mice transplanted with PDAC organoids derived from this model, were treated for 2 weeks with the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib. Induction of senescence was determined by SA-β-gal staining, and secretion of SASP factors was determined by qPCR and cytokine array. The impact on vascularization and vascular function, as well as the immune system, was determined by immunohistochemistry and flow cytometry analysis. shRNAs targeting the p65 subunit of NF-KB were used to assess the effect of SASP knockdown on treatment responses, and high doses of a VEGFR2 blocking antibody were used to assess the effects of inhibiting neovascularization on these SASP-dependent phenotypes. Trametinib and palbociclib treatment was combined with the chemotherapeutic agent gemcitabine or PD-1 checkpoint blockade immunotherapy to study the impact on tumor responses and long-term survival of PDAC tumor-bearing animals. Results: We find that therapy-induced senescence following trametinib and palbociclib treatment produces a SASP rich in proangiogenic factors, culminating in increased vascular density and perfusion in hypovascular PDAC tumors. This SASP-dependent vascular remodeling leads to enhanced drug uptake of the chemotherapeutic agent gemcitabine, and combining our senescence-inducing therapy with gemcitabine drives tumor regressions and prolonged survival in gemcitabine-refractory PDAC GEMMs and PDXs. In addition, increased antigen presentation and SASP-mediated vascular remodeling upon treatment mediates CD8+ T cell accumulation and activation within the PDAC TME, sensitizing these tumors to PD-1 checkpoint blockade. Conclusions: These results