Enhancing nanomedicine efficacy in KPC pancreatic tumors through ketotifen-mediated tumor microenvironment remodeling

Cancer immunotherapy is considered to be one of the biggest breakthroughs in cancer therapy in the last decade. However, the success of immunotherapy has so far been limited to a few solid malignancies including melanoma, renal cell carcinoma, non-small-cell lung cancer (NSCLC) and a few hematologic malignancies. In 2011, ipilimumab, a therapeutic monoclonal antibody that blocks CTLA-4, the bona fide immune checkpoint, was US FDA-approved for advanced melanoma [1]. Subsequently, other checkpoint inhibitors including anti-PD-1 and anti-PD-L1 blockade antibodies were also demonstrated to yield an objective response in approximately 20–30% of patients of these malignant diseases; and among the patients who had an objective response, many had a durable response [2–4]. One of anti-PD-1 antibodies (pembrolizumab) was most recently approved by US FDA for unresectable or metastatic melanoma. In addition, sipuleucel-T, a dendritic cell vaccine, has been shown to improve the overall survival of metastatic prostate cancer and subsequently gained FDA approval [5]. Nevertheless, significant objective response and durable responses were not seen in sipuleucel-T-treated pancreatic cancer patients. Melanoma, renal cell carcinoma and NSCLC were unique in their high infiltration of effector lymphocytes in tumor microenvironment (TME) [6]. By contrast, many other solid malignancies including pancreatic cancer are characterized by a highly immunosuppressive TME [7]. Immune tolerance mechanisms within the TME are a major obstacle to effective treatment of these cancers with immunotherapy. Pancreatic cancer and many other malignancies are thus considered ‘nonimmunogenic’ neoplasms. This notion has drastically slowed the development and application of immune-based therapies for these diseases.

Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a five-year survival rate of less than 8%. Existing therapies have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The dense desmoplastic reaction which occurs in PDAC makes it challenging for drugs and immune cells to infiltrate the fibrotic barrier. There is a need to exploit lesser explored targets in PDAC that can influence both the tumor and its microenvironment. One such avenue could be via targeting polyamine metabolism which is upregulated in pancreatic tumors. Though aberrant polyamine upregulation in pancreatic tumors has been known for decades, there has been little progress in translating this information into a PDAC therapeutic strategy. Additionally, there is a dearth of information regarding the dysregulation of polyamine metabolism in human PDAC and its association with clinical outcomes. Thus far, preclinical studies targeting polyamines using polyamine blockade therapy (PBT) has improved survival of pancreatic tumor bearing mice. Literature shows effectiveness of PBT in eliciting an anti-tumor immune response in other tumor types. Whether these results translate to the immune-privileged PDAC microenvironment need to be determined. The present study explores polyamine gene expression in human PDAC samples by mRNA expression analysis of frozen PDAC and Pancreatic intraepithelial neoplasia (PanIN). The Cancer Genome Atlas in the public domain was used to identify clinical outcomes of PDAC patients associated with select polyamine gene expression. Further, the anti-tumor effects of PBT and associated tumor microenvironment changes were identified using in vivo PDAC models and histological assessment. Polyamine dysregulation was found to be evident in human PDAC progression. Also, increased expression of certain polyamine-related genes was associated with poorer survival of pancreatic cancer patients. When targeting polyamines using PBT in immunocompetent C57Bl/6 mice with Pan02 tumor cells injected in the pancreas, PBT significantly increased overall survival. PBT also resulted in an increase in the infiltration of macrophages (F4/80) and expression of T-cell co-stimulatory marker (CD86) as assessed by immunohistochemistry and further quantification of imaging. Based on these changes, we hypothesized that PBT could prime the tumor microenvironment to be more susceptible to existing therapeutics. In conclusion, targeting polyamines using PBT results in increased survival and immune modulation in PDAC. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh G. Parikh, Dirk Geerts, Kenneth P. Olive, Otto Phanstiel, Deborah A. Altomare, Carlo Maurer. Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade therapy on the in vivo pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-120.

Decision letter: Neutrophil-mediated fibroblast-tumor cell il-6/stat-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study

A Tumor Sorting Protocol that Enables Enrichment of Pancreatic Adenocarcinoma Cells and Facilitation of Genetic Analyses

Screening for Early Pancreatic Neoplasia in High-Risk Individuals: A Prospective Controlled Study

This project aims to test the hypothesis that epigenetic modulatory drugs (EMD) and GVAX, a GM-CSF-secreting whole tumor cell vaccine, are capable of altering the inflammatory environment of pancreatic ductal adenocarcinoma (PDAC) and sensitizing it to checkpoint blocking agents. Recently the use of antibody therapy targeting immune checkpoints, such as CTLA-4 and PD-1, has become a major focus of cancer immunotherapy. In responsive patients, these therapies have resulted in long-term control of chemotherapy-resistant disease. The most compelling activity has been seen in the minority of patients with immunogenic tumors where T cell infiltration naturally occurs. These benefits are not observed in non-immunogenic tumors, such as PDAC, with low expression of tumor-associated antigens (TAA) and a lack of intrinsic T cell infiltrates. Therapies that can alter the tumor microenvironment (TME) and allow infiltration of effector T cells, decrease immunosuppressive cells, and stimulate TAA expression may convert non-immunogenic tumors into cancers sensitive to checkpoint inhibitors. Recent work with EMDs has shown that they are capable of altering the immunogenicity of the TME by inducing the expression of cancer testis antigens as well as increasing tumor cell expression of MHC class II and decreasing Tregs in the TME. Additionally, GVAX has been shown to induce tertiary lymphoid aggregates within the TME of patients with PDAC. We are testing the hypothesis that treatment with EMDs and GVAX can sensitize the inflammatory environment of PDAC to checkpoint blockade inhibition by evaluating changes in immune cell function within the TME via flow cytometry, immunohistochemistry, and gene expression array. We are using a murine model of hepatic metastases of pancreatic cancer which involves injecting syngeneic pancreatic tumor cells into the spleen followed by a hemisplenectomy, resulting in the consistent formation of hepatic metastases that can be monitored by ultrasound. We have evaluated entinostat, a histone deacetylase inhibitor, in combination with GVAX which induces T cell responses, and demonstrated a significant increase in survival when compared with either agent alone. Flow cytometric analysis of the cells infiltrating the TME shows that the combination of entinostat and GVAX causes a significant increase in CD4+ T cell infiltration as well as a shift from an M-MDSC dominant to a more G-MDSC dominant myeloid population. Current studies aim to elucidate the functionality of the MDSC population as well as identify potential changes in the T helper cell subsets via flow cytometry. Additionally, future studies will evaluate changes within checkpoint blockade pathways via flow cytometry and gene expression array to identify pathways that require further modulation to enhance antitumor responses. Citation Format: Brian Christmas, Blake Scott, Todd Armstrong, Nilofer Azad, Elizabeth Jaffee. Epigenetic modulation of the tumor microenvironment enhances vaccine induced T cell responses in a murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1686. doi:10.1158/1538-7445.AM2017-1686

There remains an urgent need to target pancreatic tumor cells using innovative strategies. KRAS and MYC, are important oncogenes in pancreatic ductal adenocarcinoma (PDAC) which pose a challenge to successful treatment of PDAC. Our previous studies have shown that inhibition of ornithine decarboxylase 1 (ODC1) using difluoromethylornithine (DFMO) decreases MYC expression and tumorigenesis. GW5074 can modulate RAF1, a downstream effector of KRAS. Here we test the responsiveness of pancreatic tumor cells treated with DFMO alone and in combination with GW5074. We used an orthotopic animal model of pancreatic tumor using KRas-driven murine pancreatic cancer cells (PanO2) to test the effects of these compounds on tumor microenvironment and overall survival. Cellular and molecular changes in the tumor microenvironment were assessed using immunohistochemistry. The results showed an inhibition of pancreatic cancer cell viability in DFMO and DFMO+GW5074 treatment groups in vitro, with a significant decrease in tumor weight compared to control treatment group in vivo. However, in terms of overall survival, DFMO alone resulted in a dramatic increase in survival compared to control treatment group. Interestingly, GW5074 alone or DFMO in combination with GW5074 did not result in a detectable effect on survival. Further investigation of immune cells in the tumor microenvironment revealed that standalone DFMO treatment was associated with an increase in infiltration of macrophages, T cell costimulatory marker CD86 and T cell markers (CD3, CD4 and CD8) compared to control and GW5074 treated groups. Additionally, DFMO is associated with decreased MYC expression compared to control and GW5074 treated groups. In conclusion, DFMO decreased MYC expression and associated immune suppression in the PDAC microenvironment. In contrast standalone GW5074 treatment resulted in maintenance of MYC expression and worse survival. In conclusion, the present study highlights the success of DFMO in PDAC treatment in part through downregulation of MYC and a decrease in associated immune suppression. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jordan M. Beardsley, Michael W. Rohr, Jignesh G. Parikh, Otto Phanstiel, Deborah A. Altomare. DFMO mediated improvement in survival of an orthotopic model of pancreatic cancer is associated with modulating immune suppression in the tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-119.

Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways

Checkpoint immunotherapeutics are promising agents with potential to improve patient outcomes in several cancer types. Unfortunately, to date, single agent immunotherapy has achieved limited clinical benefit in patients with pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of the uniquely immunosuppressive tumor microenvironment present in PDACs that creates a barrier to immune surveillance by T cells. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T cell infiltration and high numbers of tumor-associated immunosuppressive cells, such as MDSCs and regulatory T cells (Tregs). To understand which signaling pathways in pancreatic tumor cells might drive this suppressive tumor microenvironment, we analyzed the correlation between hyper-activated signaling molecules and tumor infiltrating leukocytes using 50 human PDAC tumor tissues. Of the pathways evaluated, we found that focal adhesion kinase (FAK) activity is elevated in human PDAC and that FAK activity correlates with highly fibrotic tumors with poor CD8+ T cell infiltration. The oral FAK kinase inhibitor VS-4718, currently in Phase I clinical evaluation, was tested to determine if it could overcome the immunosuppressive tumor microenvironment of PDAC. Single agent VS-4718 dramatically limited tumor progression resulting in a doubling of survival in the p48-CRE/KrasG12D/p53flox/+ PDAC mouse model (KPC mice). This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of FOXP3+ Tregs and tumor-infiltrating myeloid cells, and anti-tumor polarization of tumor-associated macrophages. We postulated that the desirable effects of FAK inhibition on the tumor microenvironment might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 significantly potentiated the efficacy of anti-PD-1 and anti-CTLA4 antibodies in KPC mouse models nearly tripling survival times. We next assessed the mechanism of this potentiation. We found that FAK in tumor cells regulates pro-inflammatory and pro-fibrotic cytokine secretion. Furthermore, we found that shRNA knockdown of FAK in PDAC cells results in failure of PDAC cells to induce pro-fibrotic programs in fibroblasts. Importantly, the FAK inhibitor VS-4718 and FAK shRNA in the tumor cells were each effective in increasing CD8+ cytotoxic T cell infiltration into the PDAC tumors in vivo. Taken together, these data suggest that FAK inhibition increases immune surveillance programs in PDAC tumors by overcoming the fibrotic and inflammatory microenvironment rendering tumors more responsive to immunotherapy. These data provide rationale for clinical evaluation of a FAK inhibitor in combination with a PD-1 or PD-L1 antibody in patients with pancreatic and other cancers.

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest incidence/death ratios among all neoplasms due to its late diagnosis and dominant chemoresistance. Most PDAC patients present with an advanced disease characterized by a multifactorial, inherent and acquired resistance to current anticancer treatments. This remarkable chemoresistance has been ascribed to several PDAC features including the genetic landscape, metabolic alterations, and a heterogeneous tumor microenvironment that is characterized by dense fibrosis, and a cellular contexture including functionally distinct subclasses of cancer-associated fibroblasts, immune suppressive cells, but also a number of bacteria, shaping a specific tumor microbiome microenvironment. Thus, recent studies prompted the emergence of a new research avenue, by describing the role of the microbiome in gemcitabine resistance, while next-generation-sequencing analyses identified a specific microbiome in different tumors, including PDAC. Functionally, the contribution of these microbes to PDAC chemoresistance is only beginning to be explored. Here we provide an overview of the studies demonstrating that bacteria have the capacity to metabolically transform and hence inactivate anticancer drugs, as exemplified by the inhibition of the efficacy of 10 out of 30 chemotherapeutics by Escherichia coli. Moreover, a number of bacteria modulate specific oncogenic pathways, such as Fusobacterium nucleatum, affecting autophagy and apoptosis induction by 5-fluorouracil and oxaliplatin. We hypothesize that improved understanding of how chemoresistance is driven by bacteria could enhance the efficacy of current treatments, and discuss the potential of microbiome modulation and targeted therapeutic approaches as well as the need for more reliable models and biomarkers to translate the findings of preclinical/translational research to the clinical setting, and ultimately overcome PDAC chemoresistance, hence improving clinical outcome.

Hedgehog (Hh) signaling is an important mediator of tumorigenesis of pancreatic ductal adenocarcinoma (PA). It is intriguing to explore whether Hh signaling is also involved in pancreatic cystic neoplasms, which are phenotypically different from PA. Patients with solid and pseudopapillary tumor (SPT; n = 12), mucinous cystic neoplasm (MCN; n = 18), intraductal papillary mucinous neoplasm (IPMN; n = 18), and PA (n = 20) were studied. Expression of Hh signaling molecules including sonic Hh (sHh), smoothened (Smo), patched 1 (Ptc1), and Gli were determined using immunohistochemistry and/or Western blotting. Cell cycle-regulator genes, including cyclin A, B, C, and D1 messenger RNA, were determined using ribonuclease protection assay. Six of 12 SPT, 8 of 18 MCN, 17 of 18 IPMN, and 20 of 20 PA displayed Hh signaling using immunohistochemistry. Sonic Hh was predominantly expressed in stromal cells neighboring to the neoplastic cells of SPT and IPMN; in contrast, sHh was expressed in both stromal cells and neoplastic epithelial cells of MCN and PA. The quantitative expression of sHh signaling detected by Western blotting showed that expression of Ptc1 and Gli, but not Smo, corresponded to the magnitude of sonic hedgehog ligand. The expression of cyclin D1 messenger RNA was highest in PA, followed by MCN, IPMN, and SPT, which matches with Ptc1 and Gli. Hedgehog signaling pathway might play a role during tumorigenesis of SPT, MCN, IPMN, and PA. Mucinous cystic neoplasm and PA exhibit an autocrine regulation of sHh, whereas SPT and IPMN do not. Overexpression of Ptc1 and Gli, reflected by cyclin D1, might represent proliferative potential of various pancreatic neoplasms.

BackgroundInfiltration of myeloid-derived suppressor cells (MDSCs) establishes an immune-suppressive tumor microenvironment (TME) in Pancreatic Ductal Adenocarcinoma (PDAC), exacerbated by chronic inflammation and recurrent gemcitabine (GEM) mediated chemotherapy. Consequently, developing an...

Arginine is an amino acid critical for various cellular processes, not only protein synthesis but also metabolism of other essential metabolites, like polyamines, as well as a signaling factor for pathways such as the growth regulator mTOR. Previously, our group measured arginine levels in the interstitial fluid of tumors (TIF) of pancreatic ductal adenocarcinoma (PDAC) murine models and found extremely low arginine levels (2-5 uM) in the tumor microenvironment (TME). Despite near complete absence of this critical nutrient in the TME, pancreatic tumors exhibit aggressive growth. We have sought to understand both how the PDAC TME becomes arginine limited and how PDAC cells adapt to proliferate in the absence of arginine. Using genetically engineered mice, we find that arginase activity in the myeloid compartment of PDAC tumors is responsible for arginine depletion in the TME. Staining of Arg1+ myeloid populations in human PDAC samples suggest a similar mechanism reduces arginine availability in human PDAC tumors as well. We then leveraged our newfound knowledge of PDAC TIF composition to develop a novel ex vivo cell culture media formulation with physiologically relevant nutrient levels and monitored arginine acquisition pathways using isotope tracing and metabolomics assays to determine how PDAC cells cope with arginine deprivation. Under TME nutrient conditions, PDAC cells consume available citrulline and use it to produce arginine by de novo synthesis. Starving cells of citrulline or genetically perturbing arginosuccinate synthase (ASS1), key enzyme in arginine biosynthesis, significantly reduces PDAC cellular arginine and proliferative capacity. Immunohistochemical analysis of both human and mouse PDAC tumors indicates that the de novo arginine synthesis pathway is highly expressed in PDAC but not in untransformed pancreas, suggesting a key role for this pathway in PDAC progression. Altogether, we find that myeloid-derived arginase challenges PDAC cells by limiting arginine availability and suggest that de novo arginine synthesis may be a critical metabolic pathway that enables PDAC tumors to cope with this metabolic challenge. Citation Format: Juan Apiz-Saab, Alex Muir. Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2177.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, the five-year survival rate of PDAC patient is around ten percent. It is fourth largest cause of cancer related death and is projected to become the second deadliest cancer by 2030. PDAC patients generally present with advanced stage, metastatic disease that is mostly resistant to chemotherapy, radiation, and immunotherapy. A significant finding is that mutant KrasG12D (Kras*) is the primary oncogenic driver of PDAC development, and therefore efforts have been devoted to target KRAS. Here, we show in pancreatic ductal adenocarcinoma (PDAC), oncogenic KrasG12D (Kras*) increases the expression of IL33, a damage-associated molecular pattern (DAMP) molecule, member of IL1 cytokine family protein and localized in the PDAC cell nucleus, which upon secretion, chemoattracts the type 2 immunocytes. Type 2 immune cells—TH2, eosinophils and innate lymphoid cells (ILC)2, stimulate tumor growth by secreting pro-tumorigenic cytokines such as IL4, IL5 and IL13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment (TME) are unknown. Cancer cell-specific deletion of IL33 leads to a significant reduction in TH2 and ILC2 recruitment and lead to tumor regression. Further, we discovered that the release of IL33 requires interactions between cancer cells and the intratumoral mycobiome. PDA tumors harbors a ~3000-fold higher fungal load compared to normal pancreas in both mouse and humans. However, the mechanism of fungal mediated cytokine release is still unknown and represents a target for limiting IL33 release, and lessening PDAC tumor burden. Genetic deletion of IL33 alone or fungal depletion leads to a decrease in TH2 and ILC2 infiltration along with robust tumor regression. Moreover, repopulation of the PDAC TME with fungal species such as Alternaria and Malassezia lead to a re-infiltration of type 2 immunocytes that reinvigorates tumor growth. Notably, transplantation of tumor-derived ILC2s into mice accelerates PDAC growth. Mechanistically fungus activates dectin-1 pathway in PDAC cancer cells, mediating the release of IL33. Consistent with the murine data, IL33 expression is upregulated in approximately 20% of human PDAC, which is mainly restricted to cancer cells. Collectively, our work shows that the intratumoral mycobiome stimulates PDAC to secrete IL33, which plays a leading role in facilitating the recruitment of type 2 immunocytes that promote tumor progression. Citation Format: Aftab Alam, Eric Levanduski, Maulasri Bhatta, Sharon Senchanthisai, Sheila Jani Sait, Jianmin Wang, Scott I. Abrams I. Abrams, Prasenjit Dey. KRAS and fungi cooperate to drive IL33 secretion and type 2 immunity in the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2119.

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 demonstrate that therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies in PDAC through SASP-dependent, non-cell autonomous effects on the tumor vasculature and immune system. This abstract is also being presented as Poster A46. Citation Format: Marcus Ruscetti, John P. Morris, IV, Riccardo Mezzadra, James Russell, Josef Leibold, Paul B. Romesser, Janelle Simon, Amanda Kulick, Yu-jui Ho, Myles Fennell, Jinyang Li, Robert J. Norgard, John E. Wilkinson, Direna Alonso-Curbelo, Ramya Sridharan, Xiang Li, Daniel Heller, Elisa de Stanchina, Ben Z. Stanger, Charles J. Sherr, Scott W. Lowe. Senescence induction triggers vascular remodeling and new vulnerabilities to chemo- and immunotherapy in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR01.