Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells

Gürlevik, Engin; Fleischmann-Mundt, Bettina; Brooks, Jennifer; Demir, Ihsan Ekin; Steiger, Katja; Ribback, Silvia; Yevsa, Tetyana; Woller, Norman; Kloos, Arnold; Ostroumov, Dmitrij; Armbrecht, Nina; Manns, Michael P.; Dombrowski, Frank; Saborowski, Michael; Kleine, Moritz; Wirth, Thomas; Oettle, Helmut; Ceyhan, Güralp O.; Espósito, Irene; Calvisi, Diego F.; Kubicka, Stefan; Kühnel, Florian

doi:10.1053/j.gastro.2016.05.004

Cited by 73 publications

(80 citation statements)

References 39 publications

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“…Our understanding of the underlying factors which contribute to disease recurrence following surgery is currently limited by the paucity of immunocompetent preclinical models of surgically resectable PDAC. The potential of such models to provide critical insights has been elegantly demonstrated in two recent publications which characterize the impact of (neo)adjuvant chemotherapy treatment on the immune system and tumor growth following surgical resection 5,6 . However, widespread implementation of this model may be limited by the challenges associated with acquiring and maintaining the transgenic mouse strain and the in vivo electroporation procedures needed for initiating tumor growth.…”

Section: Introductionmentioning

confidence: 99%

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Baxter

Souza

Tai

et al. 2020

Preprint

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Background:Although surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations. Materials and Methods:Surgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass. Results:As expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery. Conclusion:This represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.3

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Section: Introductionmentioning

confidence: 99%

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Baxter

Souza

Tai

et al. 2020

Preprint

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“…Gürlevik et al 6 extend these observations to the adjuvant treatment setting to identify a novel immunomodulatory activity for gemcitabine localized to the remnant pancreas after R0 surgical resection. Adjuvant gemcitabine selectively reduced the Cd11b + Gr1 low F4/80 + subset of MDSCs and increased the number of NK cells without altering Tregs or macrophage polarization (Figure 1).…”

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confidence: 97%

“…Gürlevik et al 6 now present a rapid and flexible system for reproducibly modeling a localized form PDA amenable to surgical resection and suitable for assessing the efficacy adjuvant systemic therapies in relation to tumor recurrence and overall survival. In this model, a plasmid carrying a Cre recombinase was electroporated using tweezers-type electrode in the pancreas of LSL-Kras-G12Dxp53fl/fl mice.…”

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confidence: 99%

“…Depletion of NK cells, but not CD8 + T cells, reversed survival advantage and inhibition of local tumor recurrence seen with gemcitabine, mechanistically linking its therapeutic action to an enhanced NK cell response after tumor resection. 6 …”

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confidence: 99%

“…Such mechanistic insights could eventually be leveraged to identify prognostic or predictive biomarkers useful in individually tailoring PDA immunotherapy regimens based on a combination of tumor profiling and immune cell analysis of tumor and/or blood samples. Finally, although not addressed in their paper, 6 this model also offers a suitable platform for exploring and validating the use of neoadjuvant therapeutic approaches before surgery, an area of intense interest and debate in the field.…”

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confidence: 99%

See 2 more Smart Citations

Gemcitabine Activates Natural Killer Cells to Attenuate Pancreatic Cancer Recurrence

Dawson

Fernández-Zapico

2016

Gastroenterology

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The double life of a chemotherapy drug: Immunomodulatory functions of gemcitabine in cancer

Larson,

Doty,

Solheim

2024

Cancer Medicine

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Although the development of immunotherapies has been revolutionary in the treatment of several cancers, many cancer types remain unresponsive to immune‐based treatment and are largely managed by chemotherapy drugs. However, chemotherapeutics are not infallible and are frequently rendered ineffective as resistance develops from prolonged exposure. Recent investigations have indicated that some chemotherapy drugs have additional functions beyond their normative cytotoxic capacity and are in fact immune‐modifying agents. Of the pharmaceuticals with identified immune‐editing properties, gemcitabine is well‐studied and of interest to clinicians and scientists alike. Gemcitabine is a chemotherapy drug approved for the treatment of multiple cancers, including breast, lung, pancreatic, and ovarian. Because of its broad applications, relatively low toxicity profile, and history as a favorable combinatory partner, there is promise in the recharacterization of gemcitabine in the context of the immune system. Such efforts may allow the identification of suitable immunotherapeutic combinations, wherein gemcitabine can be used as a priming agent to improve immunotherapy efficacy in traditionally insensitive cancers. This review looks to highlight documented immunomodulatory abilities of one of the most well‐known chemotherapy agents, gemcitabine, relating to its influence on cells and proteins of the immune system.

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Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells

Cited by 73 publications

References 39 publications

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Gemcitabine Activates Natural Killer Cells to Attenuate Pancreatic Cancer Recurrence

The double life of a chemotherapy drug: Immunomodulatory functions of gemcitabine in cancer

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