Innovate to elevate pancreatic cancer care:Immunity leading the way in precision medicine

Pancreatic cancer is an aggressive malignancy with the lowest 5-year survival rate within the field of oncology, ranking third as a cause of cancer-related death in the United States and Europe. Despite years of dedicated research into treatments for pancreatic cancer, improvements in survival rates have been marginal due to multiple challenges. The foremost factor compromising treatment efficacy is the pancreatic tumor microenvironment (TME), distinguished by its complexity, immunosuppressive nature, and patient heterogeneity. This thesis presents the results of studies aimed at unraveling the immunological landscape of pancreatic cancer and exploring avenues to guide personalized treatment options.Part I of this thesis contains four chapters delving into the immunological and molecular factors impacting the prognosis of patients with resected pancreatic cancer. The goal was to offer valuable insights facilitating the development of tailored and effective immune-based therapies, ultimately elevating patient survival. Part II of this thesis contains five chapters addressing the complexities associated with FOLFIRINOX chemotherapy, a therapeutic pillar in pancreatic cancer. The dilemma surrounding FOLFIRINOX arises due to its toxic nature affecting roughly 70% of patients, coupled with the absence of clinical benefits in 25% of cases. The goal was to examine the multifaced considerations when defining the value of FOLFIRINOX, establish predictive biomarkers for FOLFIRINOX response, and explore the potential synergy of combining immunotherapy with FOLFIRINOX to improve efficacy. Part III of this thesis contains two chapters focusing on rintatolimod, an immune-boosting drug which activates the toll-like receptor 3 (TLR-3), as a potential treatment for advanced pancreatic cancer patients. The goal was to investigate the direct effect of rintatolimod on tumorigenesis in pancreatic cancer cells and, subsequently, the impact of rintatolimod on the peripheral immune landscape.<br/

Innovate to elevate pancreatic cancer care:Immunity leading the way in precision medicine

Pancreatic cancer is an aggressive malignancy with the lowest 5-year survival rate within the field of oncology, ranking third as a cause of cancer-related death in the United States and Europe. Despite years of dedicated research into treatments for pancreatic cancer, improvements in survival rates have been marginal due to multiple challenges. The foremost factor compromising treatment efficacy is the pancreatic tumor microenvironment (TME), distinguished by its complexity, immunosuppressive nature, and patient heterogeneity. This thesis presents the results of studies aimed at unraveling the immunological landscape of pancreatic cancer and exploring avenues to guide personalized treatment options.Part I of this thesis contains four chapters delving into the immunological and molecular factors impacting the prognosis of patients with resected pancreatic cancer. The goal was to offer valuable insights facilitating the development of tailored and effective immune-based therapies, ultimately elevating patient survival. Part II of this thesis contains five chapters addressing the complexities associated with FOLFIRINOX chemotherapy, a therapeutic pillar in pancreatic cancer. The dilemma surrounding FOLFIRINOX arises due to its toxic nature affecting roughly 70% of patients, coupled with the absence of clinical benefits in 25% of cases. The goal was to examine the multifaced considerations when defining the value of FOLFIRINOX, establish predictive biomarkers for FOLFIRINOX response, and explore the potential synergy of combining immunotherapy with FOLFIRINOX to improve efficacy. Part III of this thesis contains two chapters focusing on rintatolimod, an immune-boosting drug which activates the toll-like receptor 3 (TLR-3), as a potential treatment for advanced pancreatic cancer patients. The goal was to investigate the direct effect of rintatolimod on tumorigenesis in pancreatic cancer cells and, subsequently, the impact of rintatolimod on the peripheral immune landscape.<br/

Schone Handen: als de ene hand de andere wast

Rede, in verkorte vorm uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar met als leeropdracht Chirurgie met specifieke aandacht voor het pancreas, aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 25 juni 201

Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer:an observational study

Background: Beyond demographic and immune factors, metabolic considerations, particularly metformin’s recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors. Methods: We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens. Results: Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P &lt; .001). Conclusion: This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.</p

The role of somatostatin receptors in breast and pancreatic cancer

Somatostatin, a hormone which has an inhibitory influence on several physiological processes, is a small peptide consisting of 14 amino-acids, and was first isolated from the hypothalamus of the rat. Soon after, somatostatin was found in numerous other organs, such as the brain, stomach, intestines, pancreas, thyroid, thymus and bronchi, from which it could be extracted. Natural somatostatin has a very short half-life and can only be administered intravenously. The development of several longacting analogues of somatostatin facilitated diagnostic procedures and therapy involving somatostatin and its receptors. One of the first and best known effects of the hormone somatostatin is inhibition of the release of growth hormone by the pituitary gland. Other, mainly inhibitory effects of somatostatin have been described recently, including a direct inhibitory effect on the growth of tumour cells. Somatostatin receptors (SS-R's), present on tumour and pituitary celis, mediate this inhibitory effect as well as release of growth hormone. The analogue octreotide, used in this study, binds to SS-R's on normal and tumour cells. Autoradiography, using '251_ Tyr-octreotide, was utilized to localize receptors for somatostatin in vitro. These receptors were found in several neuroendocrine tumours, as well as in breast carcinomas and islet cell tumours of the pancreas. The aim of this study was to assess the possibility of visualizing SS-R's in vivo, using octreotide labelled with radioactive "'Indium and diethylene-triaminopentaacetic acid (DTPA) as a carrier (octreoscan)

A liquid biomarker signature of inflammatory proteins accurately predicts early pancreatic cancer progression during FOLFIRINOX chemotherapy

Background: Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. This study aims to explore the potential of a multi-omics biomarker for predicting early PDAC progression by employing an in-depth mathematical modeling approach. Methods: Blood samples were collected from 58 PDAC patients undergoing FOLFIRINOX before and after the first cycle. These samples underwent gene (GEP) and inflammatory protein expression profiling (IPEP). We explored the predictive potential of exclusively IPEP through Stepwise (Backward) Multivariate Logistic Regression modeling. Additionally, we integrated GEP and IPEP using Bayesian Kernel Regression modeling, aiming to enhance predictive performance. Ultimately, the FOLFIRINOX IPEP (FFX-IPEP) signature was developed. Results: Our findings revealed that proteins exhibited superior predictive accuracy than genes. Consequently, the FFX-IPEP signature consisted of six proteins: AMN, BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8. The signature effectively identified patients transitioning from disease control to progression early during FOLFIRINOX, achieving remarkable predictive accuracy with an AUC of 0.89 in an independent test set. Importantly, the FFX-IPEP signature outperformed the conventional CA19-9 tumor marker. Conclusions: Our six-protein FFX-IPEP signature holds solid potential as a liquid biomarker for the early prediction of PDAC progression during toxic FOLFIRINOX chemotherapy. Further validation in an external cohort is crucial to confirm the utility of the FFX-IPEP signature. Future studies should expand to predict progression under different chemotherapies to enhance the guidance of personalized treatment selection in PDAC.</p

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

This study underscores GATA6’s role in distinguishing classical and basal-like pancreatic ductal adenocarcinoma (PDAC) phenotypes. Retrospective studies associate GATA6 immunohistochemistry (IHC) expression with survival outcomes, warranting prospective validation. In a prospective treatment-naive cohort of patients with resected PDAC, GATA6 IHC proves a prognostic discriminator, associating high GATA6 expression with extended survival and the classical PDAC phenotype. However, GATA6’s prognostic significance is numerically lower after gemcitabine-based neoadjuvant chemoradiotherapy compared to its significance in patients treated with upfront surgery. Furthermore, GATA6 is implicated in immunomodulation, although a comprehensive investigation of its immunological role is lacking. Treatment-naive PDAC tumors with varying GATA6 expression yield distinct immunological landscapes. Tumors highly expressing GATA6 show reduced infiltration of immunosuppressive regulatory T cells and M2 macrophages but increased infiltration of immune-stimulating, antigen-presenting, and activated T cells. Our findings caution against solely relying on GATA6 for molecular subtyping in clinical trials and open avenues for exploring immune-based combination therapies.</p

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

This study underscores GATA6’s role in distinguishing classical and basal-like pancreatic ductal adenocarcinoma (PDAC) phenotypes. Retrospective studies associate GATA6 immunohistochemistry (IHC) expression with survival outcomes, warranting prospective validation. In a prospective treatment-naive cohort of patients with resected PDAC, GATA6 IHC proves a prognostic discriminator, associating high GATA6 expression with extended survival and the classical PDAC phenotype. However, GATA6’s prognostic significance is numerically lower after gemcitabine-based neoadjuvant chemoradiotherapy compared to its significance in patients treated with upfront surgery. Furthermore, GATA6 is implicated in immunomodulation, although a comprehensive investigation of its immunological role is lacking. Treatment-naive PDAC tumors with varying GATA6 expression yield distinct immunological landscapes. Tumors highly expressing GATA6 show reduced infiltration of immunosuppressive regulatory T cells and M2 macrophages but increased infiltration of immune-stimulating, antigen-presenting, and activated T cells. Our findings caution against solely relying on GATA6 for molecular subtyping in clinical trials and open avenues for exploring immune-based combination therapies.</p