Overexpression of Interferon-Inducible Protein 16 Promotes Progression of Human Pancreatic Adenocarcinoma Through Interleukin-1β-Induced Tumor-Associated Macrophage Infiltration in the Tumor Microenvironment.

Jing-Xian Chen,Jing-Xian Chen,Chien-Shan Cheng,Zi-Jie Chen,Ling-Ling Lv,Ling-Ling Lv,Hong-Fang Gao,Lan Zheng,Lan Zheng,Chien-Shan Cheng,Jing Xie,Jing Xie,Xiao-Heng Shen,Jia-Yue Xu,Jia-Yue Xu

doi:10.3389/fcell.2021.640786

Abstract

Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1β. Neutralization of IL-1β attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.

Highlights

Pancreatic cancer, mainly in the form of pancreatic adenocarcinoma (PAAD), is one of the most malignant human cancers worldwide
The analysis showed that the expression of IL-1β was positively correlated with the expression of IFI16, further suggesting the activation of inflammasomes in PAAD (Figure 1G)
In our study, when we measured the markers of Tumor-Associated Macrophages (TAMs), including HIF-1α, CCL2, and PECAM1, we found that gemcitabine treatment potently activated the expression of TAM markers, while knockdown of IFI16 reversed the increase in TAMs in the tumor microenvironment (Figure 6F)

Summary

Introduction

Pancreatic cancer, mainly in the form of pancreatic adenocarcinoma (PAAD), is one of the most malignant human cancers worldwide. Despite the rapid development in diagnostic technology and new treatments, PAAD is still very difficult to detect at an early stage, which results in a delayed intervention that largely causes poor prognosis in the patients (Oberstein and Olive, 2013). Surgical resection is the main optimal treatment; in patients with non-surgical PAAD, chemotherapeutic agents, such as gemcitabine, demonstrate a very poor response (Principe et al, 2020). Release and infiltration of pro-inflammatory cytokines, as well as activation of proinflammatory signaling, including NF-κB, COX-2, and TLRs, demonstrate the involvement of inflammation in PAAD (Pramanik et al, 2018). Inflammation may be a potential target for the discovery of a new therapeutic strategy for PAAD

Methods

Results

Conclusion