Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year overall survival of ∼13%. Delayed diagnosis, limited response to current treatments, and the predominance of locally advanced or metastatic disease contribute to poor outcomes. Leveraging our preclinical findings in PDAC murine models, we showed that adding losartan—an angiotensin II type-1 receptor (AT1) blocker—to FOLFIRINOX followed by chemoradiation doubled R0 resection rates to ∼70% in locally advanced PDAC in a phase II trial (NCT01821729) (PMID: 31145418). However, the patient-response was variable. Here we recapitulated this variability in orthotopic PDAC mouse models and revealed the underlying mechanism. Methods and Results: To investigate potential causes of the variable response, we mapped AT1 expression using light-sheet microscopy in AT1 reporter mice bearing orthotopic PDAC. We observed abundant AT1 throughout the tumor microenvironment. To define its functional relevance, we generated Agtr1a knockout (KO) PDAC cell lines and inducible KO mouse models. AT1 deletion in either cancer cells or stromal cells (but not α-SMA+ myCAFs or pericytes) significantly reduced tumor growth. Because losartan is a pro-drug that needs activation by liver enzymes CYP3A4 and CYP2C9, we next examined its metabolism. We subcutaneously administered two major losartan metabolites, EXP3179 and EXP3174, to orthotopic PDAC-bearing mice and found that EXP3174 mediated the anti-tumor effects of losartan. Mass spectrometry of plasma samples revealed that while some tumor-bearing mice efficiently converted losartan to its active metabolite, others showed limited or no conversion. To determine the cause, we assessed CYP2C9 and CYP3A4 activity in liver microsomes from non-metastatic PDAC-bearing mice. CYP2C9 activity was markedly reduced and inversely correlated with tumor burden, providing a mechanistic basis for differential losartan activation. Ongoing work aims to determine whether PDAC patients likewise display variable plasma levels of losartan and EXP3174. Conclusion: These findings identify impaired hepatic metabolism as a key driver of variable losartan responses in locally advanced PDAC. Mass-spectrometry-based assessment of losartan and EXP3174 levels may help determine which patients can effectively activate the drug. Given losartan’s safety and low cost, its oral administration remains appropriate for most patients; however, in individuals with compromised CYP2C9 activity, administration of the active metabolite — EXP3174 may represent a more effective therapeutic option. Citation Format: Heena Kumra, Ryo Morisue, Benjamin E. Wolf, Vasiliki Salameti, Sonu Subudhi, Nilesh P. Talele, Eric F. Zaniewski, Robert Morris, Tsion H. Tale, Karim El-Marouk, Cora Schueller, Mariagiovanna Barresi, Jennifer Schulz, Halil I. Corbali, Rieke Schleinhege, Peigen Huang, Pascal Bernatchez, Wilhelm Haas, Yves Boucher, Dai Fukumura, Rakesh K. Jain. Improving response of pancreatic cancer to losartan: Mechanistic insights and implications for personalized therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1781.

Abstract Introduction: Chronic arterial hypertension (CAH) is one of the most prevalent medical conditions worldwide and plays a causal role in cardiovascular diseases. Cancer patients with CAH have inferior outcomes compared to non-hypertensive cancer patients, especially in pancreatic ductal adenocarcinoma (PDAC). Furthermore, retrospective analyses have shown that antihypertensive therapy targeting angiotensin signaling is associated with improved oncological outcomes compared to other anti-hypertensive treatments in cancer patients. Methods and Results: To investigate this relationship, we employed a syngeneic, orthotopic PDAC model in mice with chronic hypertension induced by subcutaneously implanted osmotic minipumps delivering angiotensin II. Using highly multiplexed spectral flow cytometry, we found that chronic angiotensin II administration re-wires the anti-tumor immune response, leading to an increased presence of myeloid cells, particularly Ly6C+ monocytes, and CD206+ macrophages. Blockage of the angiotensin II receptor type I (AT1) with losartan leads to a marked decrease in tumor growth and a reduction in MDSCs. This effect was observed only with the synchronous administration of angiotensin II and losartan, not with losartan alone, and was consistent across different PDAC treatment regimens. In addition, we observed a trend toward improved tumor vessel perfusion in hypertensive mice treated with losartan, indicating vascular repair. Additional findings suggest that inhibition of the angiotensin II receptor type 2 (AT2) and the Mas receptor (which physiologically counterbalance AT1 signaling) abrogated the beneficial effect of AT1 blockade with losartan, suggesting a role for AT2 and the Mas receptor in shaping the immune microenvironment. Conclusion: Overall, our findings show that CAH reprograms the tumor microenvironment in PDAC and that inhibition of angiotensin signaling reverses these changes. This may indicate that inhibition of angiotensin signaling in cancer patients with CAH may exert its beneficial effect by reprogramming the anti-tumor immune response. Citation Format: Benjamin Wolf, Heena Kumra, Ryo Morisue, Karim El-marouk, Igor L. Gomes-Santos, Rieke Schleinhege, Tsion H. Tale, Marc Charabati, Sonu Subudhi, Dai Fukumura, Rakesh K. Jain. Angiotensin-II-induced chronic hypertension reprograms the antitumor-immune-response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2084.

Venn plots and selected GSEA pathways.

Relationship between pathological response and circulating biomarker levels in the plasma of treated patients.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by activating KRAS mutations and TP53 alterations. TP53 missense mutations lose their wild-type tumor-suppressor function. Here, we studied whether p53 missense mutations have potential gain-of-function oncogenic roles and their impact on cancer-cell-intrinsic gene expression and the tumor immune microenvironment (TME) in PDAC. p53R172H established an immunosuppressive TME and impaired the efficacy of immune checkpoint inhibitors (ICIs) by regulating a distinct set of chemokines. Among these, tumor-specific reduction of Cxcl1, which encodes a chemoattractant for neutrophils, promoted T cell infiltration and decreased tumor growth. Mechanistically, p53R172H occupied the distal enhancers of Cxcl1 and amplified its expression. These enhancers were responsible for Cxcl1 expression and were essential for its immunosuppressive function. Nuclear factor κB (NF-κB) was a critical cofactor required for p53R172H occupancy at these enhancers. Thus, a common mutation in a tumor-suppressor transcription factor appropriates enhancers, thereby stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

Longitudinal analysis of circulating biomarkers in the plasma of treated patients.

Losartan+FFX+CRT and FFX+CRT gene correlation with overall survival (OS).

Immunofluorescence staining of residual PDAC in pathological responders and non-responders in FFX+CRT and losartan+FFX+CRT.

Heatmap showing differentially expressed genes (DEGs) and their expression in each patient in FFX+CRT and losartan+FFX+CRT-treated groups.

Quantitative analysis of immunofluorescence staining in PDAC lesions from FFX+CRT-treated patients.

Top 30 upregulated and 30 downregulated genes in treatment group versus untreated.

Elastic fibers are key extracellular components, providing elasticity to blood vessels, lungs, skin, and bladder. Elastic fiber formation requires the accessory proteins fibulin-4, fibulin-5, and the long and short isoforms of the latent TGFβ binding protein-4 (LTBP-4L/S). We established two molecular axes, LTBP-4L/fibulin-4 and LTBP-4S/fibulin-5, defined similar and distinct functions, and determined the role of N-linked glycans in this context. Glycoproteomic analysis identified the specific N-linked glycans in these proteins. Biophysical analyses revealed that the N-linked glycans of LTBP-4L, but not fibulin-4, were critical for fibulin-4-mediated conformational extension of LTBP-4L, impacting its function and assembly. Biochemical and recombinant removal of N-linked glycans from fibulin-4 enhanced its interaction with tropoelastin and elastic fiber formation, indicating an inhibitory role for these N-glycans. Fibulin-5 strongly interacted with and robustly induced a conformational extension of LTBP-4S, leading to enhanced binding to fibronectin, increased LTBP-4S deposition, and doubling of elastic fiber formation. Loss of N-linked glycans from fibulin-5, but not LTBP-4S, reduced their interaction by about 10-fold and abolished the ability of fibulin-5 to extend LTBP-4S conformationally. The presence of fibulin-5-extended LTBP-4S did not trigger tropoelastin aggregation in an in vitro assembly assay but boosted elastic fiber-like assembly massively when fibulin-4 and LTBP-4L were additionally present, suggesting synergistic effects. N-linked glycans in fibulin-5 were essential in this process. The study uncovers novel mechanisms that regulate elastic fiber formation, including overlapping and distinct roles of the LTBP-4L/fibulin-4 and the LTBP-4S/fibulin-5 axes and the importance of N-linked glycans of each of these proteins.

Quantitative analysis of immunofluorescence staining in PDAC lesions from FFX+CRT and losartan+FFX+CRT-treated groups.

Differentially expressed genes (DEG) in losartan+FFX+CRT versus FFX+CRT, losartan+FFX+CRT versus untreated, and FFX+CRT versus untreated.

Background Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC). Moreover, ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity. Finally, obesity is a risk factor in PDAC that may differentially modulate ICB efficacy in a malignancy-dependent manner.Methods We investigated the mechanisms underlying irAEs induced by dual ICB therapy and sought to identify strategies to mitigate them while improving ICB efficacy in the obese setting. To this end, we used a clinically relevant mouse model that integrated key features of human PDAC: (1) high-fat diet-induced obesity, (2) an orthotopic PDAC, and (3) a therapeutic regimen combining chemotherapy (FOLFIRINOX) with ICBs (α-programmed cell death protein-1 + α-cytotoxic T-lymphocyte associated protein-4 antibodies).Results Obese mice developed cardiac irAEs and had elevated serum interleukin (IL)-1β levels after chemoimmunotherapy. IL-1β blockade not only prevented myocarditis and reduced cardiac fibrosis but also enhanced the antitumor efficacy of the combination of chemotherapy plus dual ICB therapy and significantly improved the overall survival of PDAC-bearing obese mice.Conclusions Our findings provide the rationale and compelling data to test a Food and Drug Administration-approved anti-IL-1β antibody in combination with chemotherapy and dual ICB therapy in patients with pancreatic cancer with obesity.

Gene sets associated with overall survival in losartan+FFX+CRT and FFX+CRT-treated groups.

Immunofluorescence staining and quantitative analysis in PDAC lesions from losartan+FFX+CRT-treated patients.

Effect of losartan+FFX+CRT and FFX+CRT on genes involved in angiogenesis and the migration and maturation of DCs.

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.