Prophylactic dendritic cell vaccination controls pancreatic cancer growth in a mouse model

doi:10.1016/j.jcyt.2019.12.001

Cytotherapy

Volume 22, Issue 1, January 2020, Pages 6-15

https://doi.org/10.1016/j.jcyt.2019.12.001 Get rights and content

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths with high recurrence after surgery due to a paucity of effective post-surgical adjuvant treatments. DC vaccines can activate multiple anti-tumor immune responses but have not been explored for post-surgery PDAC recurrence. Intraperitoneal (IP) delivery may allow increased DC vaccine dosage and migration to lymph nodes. Here, we investigated the role of prophylactic DC vaccination controlling PDAC tumor growth with IP delivery as an administration route for DC vaccination.

Methods

DC vaccines were generated using ex vivo differentiation and maturation of bone marrow–derived precursors. Twenty mice were divided into four groups (n = 5) and treated with DC vaccines, unpulsed mature DCs, Panc02 lysates or no treatment. After tumor induction, mice underwent three magnetic resonance imaging scans to track tumor growth. Apparent diffusion coefficient (ADC), a quantitative magnetic resonance imaging measurement of tumor microstructure, was calculated. Survival was tracked. Tumor tissue was collected after death and stained with hematoxylin and eosin, Masson's trichrome, terminal deoxynucleotidyl transferase dUTP nick end labeling and anti-CD8 stains for histology.

Results

DC-vaccinated mice demonstrated stronger anti-tumor cytotoxicity compared with control groups on lactate dehydrogenase assay. DC vaccine mice also demonstrated decreased tumor volume, prolonged survival and increased ΔADC compared with control groups. On histology, the DC vaccine group had increased apoptosis, increased CD8+ T cells and decreased collagen. ΔADC negatively correlated with % collagen in tumor tissues.

Discussion

Prophylactic DC vaccination may inhibit PDAC tumor growth during recurrence and prolong survival. ΔADC may be a potential imaging biomarker that correlates with tumor histological features.

Section snippets

Translational Relevance

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths with high recurrence after surgery due to a paucity of effective post-surgical adjuvant treatments. Dendritic cell (DC) vaccines can activate multiple anti-tumor immune responses but have not been explored for PDAC treatment. Also, no standard delivery route has been established for DC vaccination, but intraperitoneal (IP) delivery is of particular interest because it allows increased DC vaccine dosage

Cell lines and media

The Panc02 mouse cell line is derived from amethylcholanthrene-induced PDAC tumors in C57BL/6 mice and was purchased from the American Type Culture Collection (ATCC; Rockville, MD, USA). Panc02 was cultured in 2 mmol/L L-glutamine RPMI 1640 media supplemented with 10% fetal bovine serum (FBS), 100 µg/mL penicillin and 100 µg/mL streptomycin (Gibco, Waltham, MA, USA). All cells were maintained in a humidified environment with 5% CO₂ at 37°C. Cell viability was checked using trypan blue staining

Generation of PDAC-specific DC vaccines

Cells differentiated from BMDCs were assessed for DC purity and maturity using FACS. Mature DCs were identified as MHCII+/CD11c+/CD86+, whereas iDCs were identified as MHCII+/CD11c+/CD86-. After culturing in RPMI with IL-4 and GM-CSF, DCs were found to stain negatively for CD86 and positively for MHC-II and CD11c; 86%, 98% and 91% of DCs stained positively for CD86, CD11c and MHC-II, respectively, when cultured with Panc02 lysates as well as IFN-γ, LPS, IL-4 and GM-CSF (Figure 1B). Mature DCs

Discussion

Although many studies have previously explored DC vaccination for treatment of pancreatic cancers [27,[45], [46], [47], [48], [49]], few studies have investigated the role of DC vaccines for prevention of tumor development and/or recurrence. In this study, we used a murine model of PDAC to show that clinically translatable preventative IP DC vaccination can effectively diminish tumor growth and that ADC can be used as an imaging biomarker for assessment of preventive DC vaccination therapeutic

Declaration of Competing Interest

This study was supported by the National Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fischel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. The authors declare no potential conflicts of interest.

Author Contributions

Conception and design of the study: ZZ, VY, and NS. Acquisition of data: AS, LP, MF, CS, BW, QM, and JY. Analysis and interpretation of data: AS, LP, YV, AE, SH, JY, and ZZ. All authors were involved in drafting or revising the manuscript. All authors have approved the final article.

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In PDAC, three major types of therapeutic vaccines have reached clinical trials, including whole-cell vaccines, peptide vaccines, and dendritic cell (DC) based vaccines [275]. Preliminary studies are easier to conduct with DC-based vaccines because antigen-loaded DCs from the same mouse strain can be used to investigate the efficacy in an allograft mouse model or in a KPC mouse to analyze cytokine release, T cell activation, and anti-tumor effects [58,276]. However, the anti-tumor immune response needs to be validated in human subjects.
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Full-Length ArticleBasic ResearchProphylactic dendritic cell vaccination controls pancreatic cancer growth in a mouse model

Abstract

Purpose

Methods

Results

Discussion

Section snippets

Translational Relevance

Cell lines and media

Generation of PDAC-specific DC vaccines

Discussion

Declaration of Competing Interest

Author Contributions

Gastrointest Endosc

Trends Immunol

Mol Ther

Clinical immunology (Orlando, Fla)

Int Immunopharmacol

Neoplasia

Cancer Lett

Vaccine

Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database

Cancer

Primary advanced unresectable pancreatic cancer

Recent Results Cancer Res

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine

N Engl J Med

Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases

Cancer Chemother Pharmacol

Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial

Oncologist

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer

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Cancers (Basel)

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Cancers (Basel)

Results of 100 pancreatic radiofrequency ablations in the context of a multimodal strategy for stage III ductal adenocarcinoma

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Anticancer Res

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Full-Length Article
Basic Research
Prophylactic dendritic cell vaccination controls pancreatic cancer growth in a mouse model