Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer‐Autonomous DNA‐Sensing Signaling Axis

Abstract

Smad4, a key mediator of the transforming growth factor‐β signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4‐deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell‐depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING‐mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4‐deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon‐alpha receptor‐deficientmice or cDC1‐deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor‐intrinsic DNA damage‐elicited type I interferon signaling.

SMAD4 regulates the progression of cholangiocarcinoma by modulating the expression of STING1

“…However, there is currently no evidence to suggest that SMAD4 gene mutations are specifically associated with the response to tumour immunotherapy. Previous studies have shown that SMAD4 gene mutation can increase the immunogenicity of pancreatic cancer through the tumour's endogenous DNA sensing system 36 . Therefore, we propose a hypothesis that the low responsiveness of CCA with SMAD4 mutation to immunotherapy may be caused by the absence of its endogenous DNA sensing system.…”

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

“…Despite these analogical insights, other studies showed conflicting results. Recently, Xiong et al demonstrated that the absence of SMAD4 promotes tumor cell immunogenicity and may trigger activation of subsequent CD8 + T cells for tumor control ( 42 ). In addition, according to Li et al, SMAD4-depletion significantly augmented anti-tumor immunity ( 43 ).…”

CDK1-SRC Interaction-Dependent Transcriptional Activation of HSP90AB1 Promotes Antitumor Immunity in Hepatocellular Carcinoma

“…Fluorescence data were obtained on a BD LSR Fortesa cell analyzer (BD Biosciences, Franklin Lakes, NJ) and analyzed using FlowJo Version 10. The number of cells counted by FCM analysis was divided by the weight of the tumor to obtain the number of cells per gram of tumor. − …”