Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion

Gan, Li-Lian; Hii, Ling‐Wei; Wong, Shew Fung; Leong, Chee‐Onn; Wu, Chun

doi:10.3390/cancers12071872

Cited by 21 publications

(24 citation statements)

References 155 publications

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“…In concert with the KRAS mutation, alterations in environmental, genetic and molecular levels, such as hypoxia, LKB1 mutation, PTEN loss, PIK3CA activation, WNT/β-catenin activation, FAK activation and MYC proto-oncogene (MYC) activation also contribute to immune suppression in PDAC tumors [ 29 , 30 ] ( Figure 1 ). For example, hypoxia can activate HIF-1α, and moreover, HIF-1α activation is potent in inducing tumoral angiogenesis by increasing the expression of VEGF [ 48 ].…”

Section: The Kras Mutation and Immune Environment In Pdacmentioning

confidence: 99%

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KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Gao

Chang

2021

Cancers

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Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

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Section: The Kras Mutation and Immune Environment In Pdacmentioning

confidence: 99%

“…Metabolic reprogramming of glucose and cell autophagy [13,14]; 4. In concert with other events, TP53 inactivation [15], LKB1 mutation [29,30], PTEN loss [29,30], WNT/β-catenin activation [29,30], FAK activation [29,30], PIK3CA activation [29,30]…”

Section: Pdac Crac Luacmentioning

confidence: 99%

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Gao

Chang

2021

Cancers

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“…Pancreatic cancer is a lethal disease that has a limited response to cytotoxic chemoradiotherapy [14,15] and even newer immunotherapies [2,3]. The limited success of immunotherapy in pancreatic cancer is likely due to the numerous immunosuppressive pathways upregulated in the hypoxic tumor microenvironment [16,17]. Hypoxia in pancreatic tumors is heterogeneous and exacerbates the complex immunosuppressive environment [18].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Assessment of Hypoxia Levels in Pancreatic Tumors Using a Dual-Modality Ultrasound/Photoacoustic Imaging System

et al. 2021

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Noninvasive anatomical and functional imaging has become an essential tool to evaluate tissue oxygen saturation dynamics in preclinical or clinical studies of hypoxia. Our dual-wavelength technique for photoacoustic (PA) imaging based on the differential absorbance spectrum of oxyhemoglobin (oxy-Hb) and deoxyhemoglobin (deoxy-Hb) can quantify tissue oxygen saturation using the intrinsic contrast property. PA imaging of tissue oxygen saturation can be used to monitor tumor-related hypoxia, which is a particularly relevant functional parameter of the tumor microenvironment that has a strong influence on tumor aggressiveness. The simultaneous acquisition of anatomical and functional information using dual-modality ultrasound (US) and PA imaging technology enhances the preclinical applicability of the method. Here, the developed dual-modality US/PA system was used to measure relative tissue oxygenation using the dual-wavelength technique. Tissue oxygen saturation was quantified in a pancreatic tumor mouse model. The differences in tissue oxygenation were detected by comparing pancreatic samples from normal and tumor-bearing mice at various time points after implantation. The use of an in vivo pancreatic tumor model revealed changes in hypoxia at various stages of tumor growth. The US/PA imaging data positively correlated with the results of immunohistochemical staining for hypoxia. Thus, our dual-modality US/PA imaging system can be used to reliably assess and monitor hypoxia in pancreatic tumor mouse models. These findings enable the use of a combination of US and PA imaging to acquire anatomical and functional information on tumor growth and to evaluate treatment responses in longitudinal preclinical studies.

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“…Because the early detection of pancreatic tumors is relatively difficult, only as few as 20% of patients are eligible for possible radical surgery; in addition, chemotherapy and radiotherapy do not substantially improve overall survival (OS) ( Martinez-Bosch et al, 2018 ). However, since immunotherapy was declared a breakthrough approach in 2013, the effectiveness of immune checkpoint inhibition has been demonstrated in various solid tumors, and it may be beneficial in pancreatic cancer ( Gan et al, 2020 ). Clinical studies of immunotherapy for pancreatic cancer are ongoing ( Zhang and Choi, 2015 ; Martinez-Bosch et al, 2018 ), and the characterization of immunophenotypes and identification of novel immune-related therapeutic targets in pancreatic cancer are urgent research goals ( Luedke et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

YAP1 is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Pancreatic Cancer

Sun

Zhang

Liu³

et al. 2021

Front. Mol. Biosci.

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Yes-associated protein-1 (YAP1) is an important effector of the Hippo pathway and has crosstalk with other cancer signaling pathways. It induces an immunosuppressive tumor microenvironment by activating pathways in several cellular components. However, the mechanisms by which it drives immune infiltration in pancreatic cancer remain poorly understood. We analyzed the expression of YAP1 as well as its prognostic value and correlations with immune infiltrates in various cancers, with a focus on pancreatic cancer. In particular, using the Oncomine database and Gene Expression Profiling Interactive Analysis (GEPIA) database, we found that YAP1 is differentially expressed between tumor tissues and control tissues in a number of cancers and in particular, is elevated in pancreatic cancer. Using the Kaplan–Meier plotter, GEPIA, and Long-term Outcome and Gene Expression Profiling database of pan-cancers (LOGpc), we further established the prognostic value of YAP1. We found that YAP1 expression was significantly related to outcomes in multiple types of cancer based on data from The Cancer Genome Atlas, particularly in pancreatic cancer. Correlations between YAP1 and immune cell infiltration and immune cell marker expression were examined using Tumor Immune Estimation Resource and GEPIA. High expression levels of YAP1 were significantly associated with a variety of immune markers and immune cell subsets in pancreatic cancer. These results suggest that YAP1 is correlated with patient outcomes and tumor immune cell infiltration in multiple cancer types and is a valuable prognostic biomarker in pancreatic cancer.

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Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion

Cited by 21 publications

References 155 publications

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

In Vivo Assessment of Hypoxia Levels in Pancreatic Tumors Using a Dual-Modality Ultrasound/Photoacoustic Imaging System

YAP1 is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Pancreatic Cancer

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