Abstract
Pancreatic cancer is among the most aggressive malignancies associated with chronic inflammation. Moreover, cellular immunity can be inhibited by inflammation induced by nucleotide-binding domain, leucine-rich family, pyrin-containing 3 (NLRP3) inflammasome. Accordingly, NLRP3 inhibition combining cytokine-induced killer (CIK) cells may improve antitumor efficacy. 3,4-Methylenedioxy-β-nitrostyrene (MNS) was selected as a specific NLRP3 inflammasome inhibitor. Western blot was used to evaluate the NLRP3 inflammasome expression in pancreatic cancer cell lines SW1990 and PANC-1. The impact of NLRP3 inhibition on migration, invasiveness, and proliferation of pancreatic cancer cells was analyzed through wound healing assay, Transwell assay, and Cell Counting Kit-8 (CCK-8) assay, respectively. The combining antitumor effect in vivo of CIK and NLRP3 inhibition was evaluated in a subcutaneous human pancreatic cancer BALB/c nude mouse model. Western blot analysis showed significant expression of NLRP3 inflammasome in human pancreatic cancer lines SW1990 and PANC-1, and MNS did significantly inhibit the expression of NLRP3 inflammasome in cell lines. Moreover, NLRP3 inhibition could significantly decrease the migration, invasiveness, and proliferation of pancreatic cancer cells. In vivo experiments showed that combination treatment with MNS and CIK cells had the greatest antitumor effect among the four treatment groups including control, MNS, and CIK. Combination treatment with NLRP3 inflammasome inhibition and CIK cells showed greater antitumor efficacy through inflammation inhibition and immunity restoration.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent and aggressive malignancies worldwide [1]
To evaluate the antitumor potential of cytokine-induced killer (CIK) cells, we analyzed the proportion of activated T cells and central memory T cells in peripheral blood mononuclear cells (PBMCs) and prepared CIK cells
The results showed that the mean percentage of activated T cells (52.62 ± 13.53% vs. 18.35 ± 10.46%, P < 0.01) and central memory T cells (42.18 ± 9.87% vs. 21.37 ± 12.73%, P < 0.05) in cultured CIK cells were dramatically higher than those of the PBMCs, respectively (Figures 1A,B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent and aggressive malignancies worldwide [1]. Despite great advance in various conventional and emerging treatment approaches, surgery remains the only curative treatment approach for localized PDAC [3]. ∼80% of patients are inoperable due to tumor metastasis [4]. Patients who underwent curative resection still suffer from high rates of perioperative morbidity and complication [5, 6]. Other therapeutic options for PDAC are not very effective due to its resistance [7]. Conventional therapies may inhibit immune function and activate inflammation [8,9,10,11]. Cancer patients present as aggressive inflammation and immunosuppression status [12]. Novel therapeutic strategies inhibiting tumor growth as well as restoring antitumor immunity and suppressing inflammation may exert a better antitumor effect
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