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

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.

The role of pyroptosis in modulating the tumor immune microenvironment

“…Overexpression of IFI-16 in pancreatic cancer cells induces the maturation, infiltration, and proliferation of TAM in the tumor microenvironment by activating inflammasomes and therefore increasing the release of IL-1β. Neutralization of IL-1β attenuated the effects of IFI-16 overexpression in pancreatic cancer cells on TAM [61]. Tumor cell-derived IL-1β is essential for the formation of the protumorigenic microenvironment in pancreatic cancer, which promotes the activation and secretory phenotype of quiescent PSC, increases stromal accumulation of TAM, MDSC, CD1d hi CD5 + regulatory B cells, and Th17 cells, and decreases intratumoral infiltration and activation of CD8 + cytotoxic T cells [62].…”

IFI16 Induced by Direct Interaction between Esophageal Squamous Cell Carcinomas and Macrophages Promotes Tumor Progression via Secretion of IL-1α

“…The results demonstrated the suppression of survival, growth, and migration in the IFI16-silenced ESCC cell lines compared to the siNC-transfected ESCC cell lines (Figures 2C-E and S3A). IFI16 is known to be a positive regulator of cytokine secretion [26,33,34]. Therefore, we conducted a cytokine array to identify humoral factors regulated by IFI16 in TE-11 cells transfected with siIFI16 or siNC (Figure S1A,B).…”

New Insights into LINC00346 and its Role in Disease

“…LINC00346 was also found to affect cell proliferation and survival by regulating the JAK-STAT3 signaling pathway (Yin et al, 2020). Pancreatic carcinoma is one of the most malignant tumors and has an extremely poor prognosis (Xu D. et al, 2020;Wang et al, 2020;Chen et al, 2021). Chemotherapy is an important method of adjuvant therapy in the comprehensive treatment of pancreatic cancer (Rahman et al, 2017;Zhu et al, 2019).…”