|
1
|
Zhao Y, Zhu W, Dong S, Zhang H, Zhou W. Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers. J Gastroenterol Hepatol 2025; 40:355-366. [PMID: 39780341 DOI: 10.1111/jgh.16873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/22/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND AND AIM Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers. METHODS This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes. RESULTS Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively. CONCLUSION Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.
Collapse
Affiliation(s)
- Yongqing Zhao
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Weixiong Zhu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Shi Dong
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Hui Zhang
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou, China
| |
Collapse
|
|
2
|
Rishabh K, Matosevic S. The diversity of natural killer cell functional and phenotypic states in cancer. Cancer Metastasis Rev 2025; 44:26. [PMID: 39853430 DOI: 10.1007/s10555-025-10242-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/08/2025] [Indexed: 01/26/2025]
Abstract
The role of natural killer (NK) cells as immune effectors is well established, as is their utility as immunotherapeutic agents against various cancers. However, NK cells' anti-cancer roles are suppressed in cancer patients by various immunomodulatory mechanisms which alter these cells' identity, function, and potential for immunosurveillance. This manifests in abnormal NK cell responses accompanied by changes in phenotypic or genotypic identity, giving rise to specific NK cell subsets that are either hypofunctional or, more broadly, defective in their responses. Anergy, senescence, and exhaustion are some of the terms that have been used to define and characterize these NK cell functional states. These responses vary not only with cancer type but also NK cell location within tissues. Collectively, these phenomena suggest a highly plastic nature of NK cell biology in tumors. In this review, we present and discuss a summary of these functionally distinct states and provide an overview of how NK cells behave at different locations within the context of cancer.
Collapse
Affiliation(s)
- Kumar Rishabh
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA
| | - Sandro Matosevic
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA.
- Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
| |
Collapse
|
|
3
|
Yu J, Huang L, Dong T, Cao L. Prediction of outcomes after chemoradiotherapy for cervical cancer by neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. J OBSTET GYNAECOL 2024; 44:2361858. [PMID: 38864403 DOI: 10.1080/01443615.2024.2361858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 05/24/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Cervical cancer ranks as the second most fatal tumour globally among females. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been widely applied to the diagnosis of cancers. METHODS The clinicopathologic data of 180 patients with stage IB2-IIB cervical cancer who underwent radical concurrent chemoradiotherapy from January 2018 to December 2019 were retrospectively analysed. Receiver operating characteristic (ROC) curves were plotted to analyse the optimal cut-off values of NLR and PLR for predicting the therapeutic effects of concurrent chemoradiotherapy. The associations of PLR and other clinicopathological factors with 1-year survival rates were explored through univariate analysis and multivariate Cox regression analysis, respectively. RESULTS NLR was significantly associated with the therapeutic effects of neoadjuvant therapy, with the optimal cut-off value of 2.89, area under the ROC curve (AUC) of 0.848 (95% confidence interval [CI]: 0.712-0.896), sensitivity of 0.892 (95% CI: 0.856-0.923) and specificity of 0.564 (95% CI: 0.512-0.592). PLR had a significant association with the therapeutic effects of neoadjuvant therapy, with the optimal cut-off value of 134.27, AUC of 0.766 (95% CI: 0.724-0.861), sensitivity of 0.874 (95% CI: 0.843-0.905) and specificity of 0.534 (95% CI: 0.512-0.556). Lymphatic metastasis ([95% CI: 1.435-5.461], [95% CI: 1.336-4.281], depth of invasion ([95% CI: 1.281-3.546], [95% CI: 1.183-3.359]) and tumour size ([95% CI: 1.129-3.451], [95% CI: 1.129-3.451]) were independent factors influencing the overall survival and disease-free survival (DFS) of patients with cervical cancer. NLR (95%CI: 1.256-4.039) and PLR (95%CI:1.281-3.546) were also independent factors affecting DFS. CONCLUSION NLR and PLR in the peripheral blood before treatment may predict DFS of patients with stage IB2-IIB cervical cancer.
Collapse
Affiliation(s)
- Jing Yu
- Department of Gynecological Oncology, Jiujiang, Jiangxi Province, China
| | | | - Ting Dong
- Department of Gynecological Oncology, Jiujiang, Jiangxi Province, China
| | - Lihua Cao
- Department of Nursing, Jiujiang, Jiangxi Province, China
| |
Collapse
|
|
4
|
Zhao Q, Zhong X, Wang X, Li B, Xu Y, Yu J, Wang L. Clinical multi-dimensional prognostic nomogram for predicting the efficacy of immunotherapy in NSCLC. Sci Rep 2024; 14:21380. [PMID: 39271765 PMCID: PMC11399400 DOI: 10.1038/s41598-024-72760-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 09/10/2024] [Indexed: 09/15/2024] Open
Abstract
The advent of immunotherapy has greatly improved the prognosis of non-small cell lung (NSCLC) patients. However, given its low response rate and high cost of treatment, the search for valuable predictive markers of treatment efficacy is necessary. Considering the complexity and heterogeneity of the tumour and tumour microenvironment, the construction of a multi-dimensional prediction model is necessary. Therefore, we aimed to integrate clinical parameters, radiomic features, and immune signature data from NSCLC patients receiving immunotherapy to construct a multi-dimensional prediction model to better predict the efficacy of immunotherapy. The current study enrolled 137 NSCLC patients who received immunotherapy. We collected baseline clinical information, CT images, and tumour tissue specimens. Using 3D-Slicer software, radiomic features were extracted from patient CT images, and tumor tissue samples obtained before immunotherapy were subjected to immunohistochemical staining. Then, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to downscale the data, and the radiomic features and immune signatures associated with the prognosis of immunotherapy patients were identified. The modified lung immune predictive index (mLIPI), radiomics score (Radioscore), immune score and multi-dimensional model nomogram were constructed. The C-index and area under the curve (AUC) were applied to evaluate the predictive efficacy of the models. Three radiomic features and three immune signatures that could predict the efficacy of immunotherapy were eventually screened. Multivariate analysis showed that the mLIPI, Radioscore, and immune score were independent predictive factors for PFS and OS (P < 0.05 for all models). The multi-dimensional model combining the three models showed better predictive efficacy than the mLIPI, Radioscore, and immune score (PFS: 0.721 vs. 0.662 vs. 0.610 vs. 0.610; OS: 0.727 vs. 0.661 vs. 0.601 vs. 0.602 respectively). The multi-dimensional model showed the best predictive efficacy, with C-index for PFS and OS higher than mLIPI, radioscore and immune score: 0.721 vs. 0.662 vs. 0.610 vs. 0.610 for PFS and 0.727 vs. 0.661 vs. 0.601 vs. 0.602 for OS, respectively. The AUC for the multi-dimensional model also performed better than those of the individual models: 0.771 vs. 0.684 vs. 0.715 vs. 0.711 for PFS and 0.768 vs. 0.662 vs. 0.661 vs. 0.658 for OS, respectively. The multi-dimensional model combining the three models had better predictive efficacy than any single model and was more likely to help provide patients personalized and precision medicine.
Collapse
Affiliation(s)
- Qian Zhao
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430064, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China
| | - Xiao Zhong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China
- Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, 271016, China
| | - Xiaoqing Wang
- Department of Portal Hypertension Intervention, Shandong Public Health Clinical Center, Jinan, 250013, China
| | - Butuo Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China
| | - Yiyue Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China
| | - Jinming Yu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430064, China.
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China.
| | - Linlin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, 250117, China.
| |
Collapse
|
|
5
|
Bogut A, Stojanovic B, Jovanovic M, Dimitrijevic Stojanovic M, Gajovic N, Stojanovic BS, Balovic G, Jovanovic M, Lazovic A, Mirovic M, Jurisevic M, Jovanovic I, Mladenovic V. Galectin-1 in Pancreatic Ductal Adenocarcinoma: Bridging Tumor Biology, Immune Evasion, and Therapeutic Opportunities. Int J Mol Sci 2023; 24:15500. [PMID: 37958483 PMCID: PMC10650903 DOI: 10.3390/ijms242115500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most challenging malignancies to treat, with a complex interplay of molecular pathways contributing to its aggressive nature. Galectin-1 (Gal-1), a member of the galectin family, has emerged as a pivotal player in the PDAC microenvironment, influencing various aspects from tumor growth and angiogenesis to immune modulation. This review provides a comprehensive overview of the multifaceted role of Galectin-1 in PDAC. We delve into its contributions to tumor stroma remodeling, angiogenesis, metabolic reprogramming, and potential implications for therapeutic interventions. The challenges associated with targeting Gal-1 are discussed, given its pleiotropic functions and complexities in different cellular conditions. Additionally, the promising prospects of Gal-1 inhibition, including the utilization of nanotechnology and theranostics, are highlighted. By integrating recent findings and shedding light on the intricacies of Gal-1's involvement in PDAC, this review aims to provide insights that could guide future research and therapeutic strategies.
Collapse
Affiliation(s)
- Ana Bogut
- City Medical Emergency Department, 11000 Belgrade, Serbia;
| | - Bojan Stojanovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.); (G.B.)
- Department of General Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia;
| | - Marina Jovanovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (M.J.); (V.M.)
| | | | - Nevena Gajovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
| | - Bojana S. Stojanovic
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
| | - Goran Balovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (B.S.); (G.B.)
| | - Milan Jovanovic
- Department of Abdominal Surgery, Military Medical Academy, 11000 Belgrade, Serbia;
| | - Aleksandar Lazovic
- Department of General Surgery, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia;
| | - Milos Mirovic
- Department of Surgery, General Hospital of Kotor, 85330 Kotor, Montenegro;
| | - Milena Jurisevic
- Department of Clinical Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Ivan Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
| | - Violeta Mladenovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (M.J.); (V.M.)
| |
Collapse
|
|
6
|
Zhang J, Yang Y, Wei Y, Li L, Wang X, Ye Z. Hsa-miR-301a-3p inhibited the killing effect of natural killer cells on non-small cell lung cancer cells by regulating RUNX3. Cancer Biomark 2023:CBM220469. [PMID: 37302028 DOI: 10.3233/cbm-220469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid tumor. Natural killer (NK) cell-based immunotherapy is a promising anti-tumor strategy in various cancers including NSCLC. OBJECTIVE We aimed to investigate the specific mechanisms that regulate the killing effect of NK cells to NSCLC cells. METHODS Reverse transcription-quantitative PCR (RT-qPCR) assay was applied to measure the levels of hsa-microRNA (miR)-301a-3p and Runt-related transcription factor 3 (RUNX3). Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IFN-γ and TNF-α. Lactate dehydrogenase assay was applied to detect the killing effect of NK cells. Dualluciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to confirm the regulatory relationship between hsa-miR-301a-3p and RUNX3. RESULTS A low expression of hsa-miR-301a-3p was observed in NK cells stimulated by IL-2. The levels of IFN-γ and TNF-α were increased in NK cells of the IL-2 group. Overexpression of hsa-miR-301a-3p reduced the levels of IFN-γ and TNF-α as well as the killing effect of NK cells. Furthermore, RUNX3 was identified to be a target of hsamiR-301a-3p. hsa-miR-301a-3p suppressed the cytotoxicity of NK cells to NSCLC cells by inhibiting the expression of RUNX3. We found hsa-miR-301a-3p promoted tumor growth by suppressing the killing effect of NK cells against NSCLC cells in vivo. CONCLUSIONS Hsa-miR-301a-3p suppressed the killing effect of NK cells on NSCLC cells by targeting RUNX3, which may provide promising strategies for NK cell-based antitumor therapies.
Collapse
|
|
7
|
Hojjatipour T, Maali A, Azad M. Natural killer cell epigenetic reprogramming in tumors and potential for cancer immunotherapy. Epigenomics 2023; 15:249-266. [PMID: 37125432 DOI: 10.2217/epi-2022-0454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023] Open
Abstract
Natural killer (NK) cells are critical members of the innate lymphoid cell population and have a pivotal role in cancer eradication. NK cell maturation, development and function are tightly regulated by epigenetic modifications, which can also be recruited for cancer propagation and immune escape. NK cells have the potential to be activated against tumors through several epigenetic regulators. Given that epigenetic changes are inducible and reversible, focusing on aberrant epigenetic regulations recruited by tumor cells provides a tremendous opportunity for cancer treatment. This review presents a comprehensive picture of NK cell normal epigenetic regulation and cancer-driven epigenetic modifications. From our perspective, a better understanding of epigenetic regulators that can edit and revise NK cells' activity is a promising avenue for NK cell-based therapy in cancer management.
Collapse
Affiliation(s)
- Tahereh Hojjatipour
- Department of Hematology & Blood Transfusion, Students Research Center, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhosein Maali
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
- Department of Medical Biotechnology, School of Paramedicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mehdi Azad
- Department of Medical Laboratory Sciences, School of Paramedicine, Qazvin University of Medical Sciences, Qazvin, Iran
| |
Collapse
|
|
8
|
Jiang Z, Zhang W, Sha G, Wang D, Tang D. Galectins Are Central Mediators of Immune Escape in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:5475. [PMID: 36428567 PMCID: PMC9688059 DOI: 10.3390/cancers14225475] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/02/2022] [Accepted: 11/07/2022] [Indexed: 11/09/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is highly immune tolerant. Although there is immune cell infiltration in PDAC tissues, most of the immune cells do not function properly and, therefore, the prognosis of PDAC is very poor. Galectins are carbohydrate-binding proteins that are intimately involved in the proliferation and metastasis of tumor cells and, in particular, play a crucial role in the immune evasion of tumor cells. Galectins induce abnormal functions and reduce numbers of tumor-associated macrophages (TAM), natural killer cells (NK), T cells and B cells. It further promotes fibrosis of tissues surrounding PDAC, enhances local cellular metabolism, and ultimately constructs tumor immune privileged areas to induce immune evasion behavior of tumor cells. Here, we summarize the respective mechanisms of action played by different Galectins in the process of immune escape from PDAC, focusing on the mechanism of action of Galectin-1. Galectins cause imbalance between tumor immunity and anti-tumor immunity by coordinating the function and number of immune cells, which leads to the development and progression of PDAC.
Collapse
Affiliation(s)
- Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Wenjie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Gengyu Sha
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Daorong Wang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou 225000, China
| | - Dong Tang
- Clinical Medical College, Yangzhou University, Yangzhou 225000, China
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People’s Hospital, Yangzhou 225000, China
| |
Collapse
|
|
9
|
lncRNA MANCR Inhibits NK Cell Killing Effect on Lung Adenocarcinoma by Targeting miRNA-30d-5p. Cell Microbiol 2022. [DOI: 10.1155/2022/4928635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background. NK cells are imperative in spontaneous antitumor response of various cancers. Currently, lncRNAs are considered important modulators of the tumor microenvironment. This study investigated the molecular mechanism by which mitotically associated long noncoding RNA (MANCR) controls killing effect of NK cells on lung adenocarcinoma (LUAD) in the tumor microenvironment. Methods. The interplay between MANCR and miRNA-30d-5p was analyzed by bioinformatics. Expression of MANCR mRNA and miRNA-30d-5p was examined using qRT-PCR. Dual-luciferase reporter and RIP assays were utilized to verify the targeted relationship between MANCR and miRNA-30d-5p. To investigate regulation of MANCR/miRNA-30d-5p axis in NK cell killing effect on LUAD cells, western blot tested the protein level of perforin and granzyme B. ELISA determined the level of IFN-γ. CytoTox 96 Non-Radioactive Cytotoxicity Assay kit was applied for cytotoxicity detection of NK cells. Perforin and granzyme B fluorescence intensity was measured via immunofluorescence, and cell apoptosis levels were also revealed via flow cytometry. Results. MANCR was found to be upregulated, while miRNA-30d-5p expression was downregulated in LUAD tissues. Overexpression of MANCR in LUAD cells significantly reduced NK cell IFN-γ secretion, expression of granzyme B and perforin, and NK cell killing effect. In addition, MANCR could target and downregulate miRNA-30d-5p expression, and miRNA-30d-5p overexpression reversed the inhibition of NK cell killing effect caused by MANCR overexpression. Conclusion. MANCR inhibited the killing effect of NK cells on LUAD via targeting and downregulating miRNA-30d-5p and provided new ideas for antitumor therapy based on tumor microenvironment.
Collapse
|
|
10
|
Balázs K, Kocsis ZS, Ágoston P, Jorgo K, Gesztesi L, Farkas G, Székely G, Takácsi-Nagy Z, Polgár C, Sáfrány G, Jurányi Z, Lumniczky K. Prostate Cancer Survivors Present Long-Term, Residual Systemic Immune Alterations. Cancers (Basel) 2022; 14:3058. [PMID: 35804830 PMCID: PMC9264868 DOI: 10.3390/cancers14133058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/10/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The development of cancer and anti-tumor therapies can lead to systemic immune alterations but little is known about how long immune dysfunction persists in cancer survivors. METHODS We followed changes in the cellular immune parameters of prostate cancer patients with good prognostic criteria treated with low dose rate brachytherapy before and up to 3 years after the initiation of therapy. RESULTS Patients before therapy had a reduced CD4+ T cell pool and increased regulatory T cell fraction and these alterations persisted or got amplified during the 36-month follow-up. A significant decrease in the total NK cell number and a redistribution of the circulating NK cells in favor of a less functional anergic subpopulation was seen in patients before therapy but tumor regression led to the regeneration of the NK cell pool and functional integrity. The fraction of lymphoid DCs was increased in patients both before therapy and throughout the whole follow-up. Increased PDGF-AA, BB, CCL5 and CXCL5 levels were measured in patients before treatment but protein levels rapidly normalized. CONCLUSIONS while NK cell dysfunction recovered, long-term, residual alterations persisted in the adaptive and partly in the innate immune system.
Collapse
Affiliation(s)
- Katalin Balázs
- National Public Health Center, Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, 1221 Budapest, Hungary; (K.B.); (G.S.)
- Doctoral School of Pathological Sciences, Semmelweis University, 1085 Budapest, Hungary
| | - Zsuzsa S. Kocsis
- Department of Radiobiology and Diagnostic Onco-Cytogenetics and The National Tumorbiology Laboratory, Centre of Radiotherapy, National Institute of Oncology, 1122 Budapest, Hungary; (Z.S.K.); (G.F.); (G.S.); (Z.J.)
| | - Péter Ágoston
- Centre of Radiotherapy and The National Tumorbiology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary; (P.Á.); (K.J.); (L.G.); (Z.T.-N.); (C.P.)
- Department of Oncology, Semmelweis University, 1122 Budapest, Hungary
| | - Kliton Jorgo
- Centre of Radiotherapy and The National Tumorbiology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary; (P.Á.); (K.J.); (L.G.); (Z.T.-N.); (C.P.)
- Department of Oncology, Semmelweis University, 1122 Budapest, Hungary
| | - László Gesztesi
- Centre of Radiotherapy and The National Tumorbiology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary; (P.Á.); (K.J.); (L.G.); (Z.T.-N.); (C.P.)
| | - Gyöngyi Farkas
- Department of Radiobiology and Diagnostic Onco-Cytogenetics and The National Tumorbiology Laboratory, Centre of Radiotherapy, National Institute of Oncology, 1122 Budapest, Hungary; (Z.S.K.); (G.F.); (G.S.); (Z.J.)
| | - Gábor Székely
- Department of Radiobiology and Diagnostic Onco-Cytogenetics and The National Tumorbiology Laboratory, Centre of Radiotherapy, National Institute of Oncology, 1122 Budapest, Hungary; (Z.S.K.); (G.F.); (G.S.); (Z.J.)
| | - Zoltán Takácsi-Nagy
- Centre of Radiotherapy and The National Tumorbiology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary; (P.Á.); (K.J.); (L.G.); (Z.T.-N.); (C.P.)
- Department of Oncology, Semmelweis University, 1122 Budapest, Hungary
| | - Csaba Polgár
- Centre of Radiotherapy and The National Tumorbiology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary; (P.Á.); (K.J.); (L.G.); (Z.T.-N.); (C.P.)
- Department of Oncology, Semmelweis University, 1122 Budapest, Hungary
| | - Géza Sáfrány
- National Public Health Center, Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, 1221 Budapest, Hungary; (K.B.); (G.S.)
| | - Zsolt Jurányi
- Department of Radiobiology and Diagnostic Onco-Cytogenetics and The National Tumorbiology Laboratory, Centre of Radiotherapy, National Institute of Oncology, 1122 Budapest, Hungary; (Z.S.K.); (G.F.); (G.S.); (Z.J.)
| | - Katalin Lumniczky
- National Public Health Center, Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, 1221 Budapest, Hungary; (K.B.); (G.S.)
| |
Collapse
|
|
11
|
Fang F, Xie S, Chen M, Li Y, Yue J, Ma J, Shu X, He Y, Xiao W, Tian Z. Advances in NK cell production. Cell Mol Immunol 2022; 19:460-481. [PMID: 34983953 PMCID: PMC8975878 DOI: 10.1038/s41423-021-00808-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/06/2021] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy based on natural killer (NK) cells is a promising approach for treating a variety of cancers. Unlike T cells, NK cells recognize target cells via a major histocompatibility complex (MHC)-independent mechanism and, without being sensitized, kill the cells directly. Several strategies for obtaining large quantities of NK cells with high purity and high cytotoxicity have been developed. These strategies include the use of cytokine-antibody fusions, feeder cells or membrane particles to stimulate the proliferation of NK cells and enhance their cytotoxicity. Various materials, including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), induced pluripotent stem cells (iPSCs) and NK cell lines, have been used as sources to generate NK cells for immunotherapy. Moreover, genetic modification technologies to improve the proliferation of NK cells have also been developed to enhance the functions of NK cells. Here, we summarize the recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources. We also discuss the closed, automated and GMP-controlled large-scale expansion systems used for NK cells and possible future NK cell-based immunotherapy products.
Collapse
Affiliation(s)
- Fang Fang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Siqi Xie
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Minhua Chen
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Yutong Li
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Jingjing Yue
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Jie Ma
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Xun Shu
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Yongge He
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China
| | - Weihua Xiao
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China.
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China.
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China.
| | - Zhigang Tian
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China.
- Engineering Technology Research Center of Biotechnology Drugs Anhui, University of Science and Technology of China, Hefei, 230027, China.
- Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China.
| |
Collapse
|
|
12
|
Liu Y, Li G, Yang Y, Lu Z, Wang T, Wang X, Liu J. Analysis of N6-Methyladenosine Modification Patterns and Tumor Immune Microenvironment in Pancreatic Adenocarcinoma. Front Genet 2022; 12:752025. [PMID: 35046996 PMCID: PMC8762218 DOI: 10.3389/fgene.2021.752025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 12/10/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Pancreatic adenocarcinoma (PAAD) is a rare cancer with a poor prognosis. N6-methyladenosine (m6A) is the most common mRNA modification. However, little is known about the relationship between m6A modification and the tumor immune microenvironment (TIME) in PAAD. Methods: Based on 22 m6A regulators, m6A modification patterns of PAAD samples extracted from public databases were systematically evaluated and correlated with the tumor immune and prognosis characteristics. An integrated model called the "m6Ascore" was constructed, and its prognostic role was evaluated. Results: Three different m6Aclusters and gene clusters were successively identified; these clusters were characterized by differences in prognosis, immune cell infiltration, and pathway signatures. The m6Ascore was constructed to quantify the m6A modifications of individual patients. Subsequent analysis revealed that m6Ascore was an independent prognostic factor of PAAD and could be a potential indicator to predict the response to immunotherapy. Conclusion: This study comprehensively evaluated the features of m6A modification patterns in PAAD. m6A modification patterns play a non-negligible role in the TIME of PAAD. m6Ascore provides a more holistic understanding of m6A modification in PAAD, and will help clinicians predict the prognosis and response to immunotherapy.
Collapse
Affiliation(s)
- Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yang Yang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ziwen Lu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tao Wang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoyu Wang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| |
Collapse
|
|
13
|
Li Y, Su Z, Wei B, Qin M, Liang Z. Bioinformatics analysis identified MMP14 and COL12A1 as immune-related biomarkers associated with pancreatic adenocarcinoma prognosis. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2021; 18:5921-5942. [PMID: 34517516 DOI: 10.3934/mbe.2021296] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors with high mortality rates and a poor prognosis. There is an urgent need to determine the molecular mechanism of PAAD tumorigenesis and identify promising biomarkers for the diagnosis and targeted therapy of the disease. METHODS Three GEO datasets (GSE62165, GSE15471 and GSE62452) were analyzed to obtain differentially expressed genes (DEGs). The PPI networks and hub genes were identified through the STRING database and MCODE plugin in Cytoscape software. GO and KEGG enrichment pathways were analyzed by the DAVID database. The GEPIA database was utilized to estimate the prognostic value of hub genes. Furthermore, the roles of MMP14 and COL12A1 in immune infiltration and tumor-immune interaction and their biological functions in PAAD were explored by TIMER, TISIDB, GeneMANIA, Metascape and GSEA. RESULTS A total of 209 common DEGs in the three datasets were obtained. GO function analysis showed that the 209 DEGs were significantly enriched in calcium ion binding, serine-type endopeptidase activity, integrin binding, extracellular matrix structural constituent and collagen binding. KEGG pathway analysis showed that DEGs were mainly enriched in focal adhesion, protein digestion and absorption and ECM-receptor interaction. The 14 genes with the highest degree of connectivity were defined as the hub genes of PAAD development. GEPIA revealed that PAAD patients with upregulated MMP14 and COL12A1 expression had poor prognoses. In addition, TIMER analysis revealed that MMP14 and COL12A1 were closely associated with the infiltration levels of macrophages, neutrophils and dendritic cells in PAAD. TISIDB revealed that MMP14 was strongly positively correlated with CD276, TNFSF4, CD70 and TNFSF9, while COL12A1 was strongly positively correlated with TNFSF4, CD276, ENTPD1 and CD70. GSEA revealed that MMP14 and COL12A1 were significantly enriched in epithelial mesenchymal transition, extracellular matrix receptor interaction, apical junction, and focal adhesion in PAAD development. CONCLUSIONS Our study revealed that overexpression of MMP14 and COL12A1 is significantly correlated with PAAD patient poor prognosis. MMP14 and COL12A1 participate in regulating tumor immune interactions and might become promising biomarkers for PAAD.
Collapse
Affiliation(s)
- Yuexian Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Zhou Su
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Biwei Wei
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Mengbin Qin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, China
| | - Zhihai Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| |
Collapse
|
|
14
|
Fincham REA, Delvecchio FR, Goulart MR, Yeong JPS, Kocher HM. Natural killer cells in pancreatic cancer stroma. World J Gastroenterol 2021; 27:3483-3501. [PMID: 34239264 PMCID: PMC8240050 DOI: 10.3748/wjg.v27.i24.3483] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/06/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains one of medicine's largest areas of unmet need. With five-year survival rates of < 8%, little improvement has been made in the last 50 years. Typically presenting with advance stage disease, treatment options are limited. To date, surgery remains the only potentially curative option, however, with such late disease presentation, the majority of patients are unresectable. Thus, new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients. Natural killer (NK) cells are crucial effector units in cancer immunosurveillance. Often used as a prognostic biomarker in a range of malignancies, NK cells have received much attention as an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. Despite this interest, the role of NK cells in pancreatic cancer remains poorly defined. Nevertheless, increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light. Here, we review the role of NK cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.
Collapse
Affiliation(s)
- Rachel Elizabeth Ann Fincham
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Francesca Romana Delvecchio
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Michelle R Goulart
- Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| | - Joe Poe Sheng Yeong
- Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, United Kingdom
| |
Collapse
|
|
15
|
Xie MZ, Tang YP, Hu BL, Li KZ, Li JL, Liang XQ. Percentage of Natural Killer (NK) Cells in Peripheral Blood Is Associated with Prognosis in Patients with Gastric Cancer: A Retrospective Study from a Single Center. Med Sci Monit 2021; 27:e927464. [PMID: 33500378 PMCID: PMC7849206 DOI: 10.12659/msm.927464] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Natural killer (NK) cells are important for the prognosis of multiple cancers, but their prognostic value remains to be evaluated in patients with gastric cancer. Thus, this retrospective study was conducted at a single center to investigate the association between percentage of NK cells in the peripheral blood and prognosis in patients with gastric cancer. Material/Methods The data of 180 gastric cancer patients were collected. Univariate and multivariate Cox regression models were applied to screen candidate prognostic factors. A time-dependent receiver operating characteristic curve was employed to evaluate the ability of NK cells as a prognostic marker. Furthermore, we determined the correlation between the NK cells percentage and other parameters and their clinical significance. Results Patients with a higher percentage of NK cells survived longer than those with a lower percentage of NK cells. Cox analysis revealed that NK cells could be used as an independent indicator for patients with gastric cancer. The percentage of NK cells was positively correlated with lymphocyte count and albumin, but was negatively correlated with CA125 and neutrophil-lymphocyte ratio. The area under the curve for NK cells in predicting the 5-year survival rate for gastric cancer was 0.792. This increased to 0.830 upon combining NK cells with neutrophil-lymphocyte ratio. Patients at early T, N, and clinical stages possessed a significantly higher percentage of NK cells compared to those at advanced T, N, and clinical stages of gastric cancer. Conclusions Our results suggest that a higher percentage of NK cells predicts is associated with longer survival of gastric cancer patients and could serve as an independent prognostic biomarker.
Collapse
Affiliation(s)
- Ming-Zhi Xie
- Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Yan-Ping Tang
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Bang-Li Hu
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Ke-Zhi Li
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Ji-Lin Li
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Xin-Qiang Liang
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| |
Collapse
|
|
16
|
Mejia I, Bodapati S, Chen KT, Díaz B. Pancreatic Adenocarcinoma Invasiveness and the Tumor Microenvironment: From Biology to Clinical Trials. Biomedicines 2020; 8:E401. [PMID: 33050151 PMCID: PMC7601142 DOI: 10.3390/biomedicines8100401] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/28/2020] [Accepted: 10/03/2020] [Indexed: 12/18/2022] Open
Abstract
Pancreatic adenocarcinoma (PDAC) originates in the glandular compartment of the exocrine pancreas. Histologically, PDAC tumors are characterized by a parenchyma that is embedded in a particularly prominent stromal component or desmoplastic stroma. The unique characteristics of the desmoplastic stroma shape the microenvironment of PDAC and modulate the reciprocal interactions between cancer and stromal cells in ways that have profound effects in the pathophysiology and treatment of this disease. Here, we review some of the most recent findings regarding the regulation of PDAC cell invasion by the unique microenvironment of this tumor, and how new knowledge is being translated into novel therapeutic approaches.
Collapse
Affiliation(s)
- Isabel Mejia
- Department of Medicine, Division of Medical Hematology Oncology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
| | - Sandhya Bodapati
- College of Osteopathic Medicine, Pacific Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Kathryn T. Chen
- Department of Surgery, Division of Surgical Oncology, Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
| | - Begoña Díaz
- Department of Medicine, Division of Medical Hematology Oncology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA;
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
| |
Collapse
|
|
17
|
Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer 2020; 19:120. [PMID: 32762681 PMCID: PMC7409673 DOI: 10.1186/s12943-020-01238-x] [Citation(s) in RCA: 468] [Impact Index Per Article: 93.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.
Collapse
Affiliation(s)
- Song-Yang Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Tong Fu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
18
|
Gong Y, Fan Z, Luo G, Huang Q, Qian Y, Cheng H, Jin K, Ni Q, Yu X, Liu C. Absolute Counts of Peripheral Lymphocyte Subsets Correlate with the Progression-Free Survival and Metastatic Status of Pancreatic Neuroendocrine Tumour Patients. Cancer Manag Res 2020; 12:6727-6737. [PMID: 32848455 PMCID: PMC7425098 DOI: 10.2147/cmar.s257492] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/21/2020] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Pancreatic neuroendocrine tumours (panNETs) are rare tumours of pancreas. Lymphocyte subsets in the peripheral blood are reported to reflect tumour prognosis and progression. The objective of the study is to investigate the hypotheses that the levels of peripheral lymphocytes may reflect tumour progression and may predict the prognosis of pancreatic neuroendocrine tumours (panNETs). PATIENTS AND METHODS A retrospective cohort study consisting of 73 patients diagnosed with panNETs was conducted. Kaplan-Meier methods and Log rank tests were used to compare the survival rates, and a Cox regression model was used to perform multivariate analyses. RESULTS panNET patients with distant metastasis were associated with lower peripheral total T cell (p = 0.039) and CD4+ T cell (p = 0.006) counts. Lower peripheral B cells (p = 0.007) and higher peripheral NK cell (p = 0.001) counts indicated worse progression-free survival (PFS) in Log rank tests. In multivariate analyses, low B cell count (hazard ratio (HR): 6.769, 95% confidence interval (CI): 2.158 to 21.228, p = 0.001) and high NK cell count (HR: 3.715, 95% CI: 1.164 to 11.855, p = 0.027) were independent risk factors for progression. NK cells and B cells were also significantly associated with PFS following radical surgical resection. CONCLUSION Peripheral total T cell and CD4+ T cell counts may reflect the distant metastasis status in panNET patients. The absolute count of peripheral B cells and NK cells may independently predict the progression of panNET patients, making them promising prognostic indicators and potential targets for treatment of panNETs.
Collapse
Affiliation(s)
- Yitao Gong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Yunzhen Qian
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai200032, People’s Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai200032, People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai200032, People’s Republic of China
| |
Collapse
|
|
19
|
Zhang S, Liu W, Hu B, Wang P, Lv X, Chen S, Shao Z. Prognostic Significance of Tumor-Infiltrating Natural Killer Cells in Solid Tumors: A Systematic Review and Meta-Analysis. Front Immunol 2020; 11:1242. [PMID: 32714321 PMCID: PMC7343909 DOI: 10.3389/fimmu.2020.01242] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 05/18/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues. Methods: PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance. Results : Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315–0.710, p < 0.001; HR = 0.484, 95%CI: 0.380–0.616, p < 0.001; HR = 0.34, 95%CI: 0.14–0.80, p = 0.014; HR = 0.622, 95%CI: 0.470–0.821, p < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261–0.531, p < 0.001; HR = 0.525, 95%CI: 0.346–0.797, p = 0.003; HR = 0.559, 95%CI: 0.385–0.812, p = 0.002, respectively). Conclusions : Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.
Collapse
Affiliation(s)
- Shuo Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijian Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binwu Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
20
|
Valipour B, Velaei K, Abedelahi A, Karimipour M, Darabi M, Charoudeh HN. NK cells: An attractive candidate for cancer therapy. J Cell Physiol 2019; 234:19352-19365. [DOI: 10.1002/jcp.28657] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/17/2019] [Accepted: 03/19/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Behnaz Valipour
- Stem Cell Research Centre Tabriz University of Medical Sciences Tabriz Iran
- Department of Anatomical Sciences, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Kobra Velaei
- Department of Anatomical Sciences, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Abedelahi
- Department of Anatomical Sciences, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Mohammad Karimipour
- Department of Anatomical Sciences, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | - Masoud Darabi
- Biochemistry Department, Faculty of Medicine Tabriz University of Medical Sciences Tabriz Iran
| | | |
Collapse
|