|
1
|
Cooper ZA, Wang Y, Martin PL, Murayama K, Kumar R, Kato K, Yamamoto S, Sekine S. Quantifying CD73 expression after chemotherapy or chemoradiotherapy in esophageal squamous cell carcinoma. Discov Oncol 2025; 16:427. [PMID: 40158055 PMCID: PMC11954769 DOI: 10.1007/s12672-025-02179-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/18/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND CD73 and CD39, key components of the adenosine axis, are expressed in multiple malignancies; the impact of standard-of-care treatment on their expression and antitumor immunity in esophageal squamous cell carcinoma (ESCC) remains unclear. We evaluated the adenosine axis in the context of neoadjuvant therapy received and its relationship to immune markers in ESCC tumor samples. METHODS Samples from patients who underwent surgical resection at the National Cancer Center Hospital, Tokyo, Japan, between January 2002 and July 2019 following no neoadjuvant therapy (n = 55; treatment-naïve), chemotherapy (n = 200), or chemoradiotherapy (CRT; n = 20) were immunohistochemically stained for CD73, CD39, PD-L1, FoxP3, and CD8; markers were quantified across tumor microenvironment (TME) compartments. RESULTS Median CD73 TME expression was lower in the treatment-naïve (2.8%) versus chemotherapy (7.2%; p < 0.0001) and CRT (6.4%; p < 0.01) cohorts, most profoundly in the stroma (median 4.1% vs 9.4% [p < 0.0001] and 8.1% [p < 0.01]). Median intraepithelial CD8-positive cell density was higher in the treatment-naïve (200.7 cells/mm2) versus chemotherapy (93.9 cells/mm2; p < 0.0001) and CRT (30.5 cells/mm2; p < 0.001) cohorts. Three-year recurrence-free survival (RFS) was 73.0%, 58.0%, and 30.0%, and 3-year overall survival (OS) was 78.2%, 71.4%, and 33.5%, in the treatment-naïve, chemotherapy, and CRT cohorts, respectively. High versus low CD73 TME expression was prognostic for longer RFS (treatment-naïve cohort: hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.05-0.58, p = 0.0014; chemotherapy cohort: HR 0.52, 95% CI 0.34-0.78, p = 0.0012) and OS. CONCLUSIONS These translational data demonstrating higher CD73 expression in tumors after neoadjuvant chemotherapy or CRT support potential combination strategies with CD73-targeted treatment in ESCC.
Collapse
Affiliation(s)
- Zachary A Cooper
- Oncology R&D, AstraZeneca, 1 Medimmune Way, Gaithersburg, MD, USA.
| | - Ying Wang
- Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, USA
| | - Philip L Martin
- Oncology R&D, AstraZeneca, 1 Medimmune Way, Gaithersburg, MD, USA
| | - Kosho Murayama
- Oncology R&D, AstraZeneca K.K., 3-1 Ofuku-Cho, Kita-Ku, Osaka, 530-0011, Japan
| | - Rakesh Kumar
- Oncology R&D, AstraZeneca, 1 Medimmune Way, Gaithersburg, MD, USA
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, 5 Chome-1-1 Tsukiji, Chuo City, Tokyo, 104-0045, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, 5 Chome-1-1 Tsukiji, Chuo City, Tokyo, 104-0045, Japan
| | - Shigeki Sekine
- Department of Diagnostic Pathology, National Cancer Center Hospital, 5 Chome-1-1 Tsukiji, Chuo City, Tokyo, 104-0045, Japan
| |
Collapse
|
|
2
|
Petruk N, Wood SL, Gregory W, Lopez-Guajardo A, Oliva M, Mella M, Sandholm J, Jukkola A, Brown JE, Selander KS. Increased primary breast tumor expression of CD73 is associated with development of bone metastases and is a potential biomarker for adjuvant bisphosphonate use. Sci Rep 2025; 15:9449. [PMID: 40108234 PMCID: PMC11923362 DOI: 10.1038/s41598-025-92841-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/03/2025] [Indexed: 03/22/2025] Open
Abstract
PURPOSE Increased CD73 expression has been associated with progression in various cancer types. Results of the AZURE and other trials suggest that, in postmenopausal breast cancer patients, adjuvant bisphosphonates inhibit bone relapses and prolong overall survival. Based on these findings, adjuvant bisphosphonates (typically zoledronic acid) are standard-of-care in postmenopausal patients with high-risk early breast cancer. However, biomarkers are needed for improved patient selection. The aim of this study was to investigate the association of primary tumor CD73 expression with later development of bone metastases. METHODS To determine whether CD73 levels correlated with tumor parameters (hormone receptor status, tumor stage and grade), patient outcomes (bone metastases and survival) or other patient characteristics (menopausal status, chemotherapy or statin use), we analyzed primary breast tumor CD73 expression immunohistochemically in tumor microarray samples from the AZURE (BIG01/04) trial. RESULTS In the AZURE control arm, high CD73 score are significantly prognostic for overall survival (p-value = 0.03, HR = 1.87, 95% CI = 1.06-3.29), disease-free survival (p-value = 0.06, HR = 1.66, 95% CI = 0.982-2.8) and time to first metastasis to bone (p-value = 0.04, HR = 2.23, 95% CI = 1.04-4.81), as compared with low CD73 scores. However, high CD73 score did not display an association with time to non-bone metastasis or first recurrence to a non-skeletal site. In the zoledronate arm, high CD73 score did not have association with patient outcomes, first metastasis to bone, nor with bone recurrence at any time (distant recurrence, including skeletal) or first non-skeletal recurrence. In multivariate testing, CD73 had no significant association with age, ER status, tumor stage, histological grade, menopausal status, chemotherapy or statin use in either arm. CONCLUSIONS High CD73 expression is associated with development of bone metastases. Zoledronate counteracts this effect. These results suggest that CD73 expression might serve as a biomarker for adjuvant zoledronic acid use.
Collapse
Affiliation(s)
- Nataliia Petruk
- Institute of Biomedicine, University of Turku, Turku, Finland
- Western Cancer Centre FICAN West, Turku, Finland
| | - Steven L Wood
- Division of Clinical Medicine, Medical School, Sheffield, UK
| | - Walter Gregory
- Division of Clinical Medicine, Medical School, Sheffield, UK
| | | | - Maria Oliva
- Division of Clinical Medicine, Medical School, Sheffield, UK
| | - Mikko Mella
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Oncology and Radiation Therapy, Oulu University Hospital, Oulu, Finland
| | - Jouko Sandholm
- Turku Bioscience Centre, University of Turku, Åbo Akademi University, Turku, Finland
| | - Arja Jukkola
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Oncology, Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Janet E Brown
- Division of Clinical Medicine, Medical School, Sheffield, UK
| | - Katri S Selander
- Department of Oncology and Radiation Therapy, Oulu University Hospital, Oulu, Finland.
- Department of Translational Medicine, University of Oulu, Oulu, Finland.
| |
Collapse
|
|
3
|
Yuan Z, Wang JH, Cui H, Wang SY, Wei B, Cui JX. Mapping the landscape of gastric cancer immunotherapy: Bibliometric insights into advances and hotspots. World J Gastrointest Oncol 2025; 17:100997. [PMID: 40092931 PMCID: PMC11866247 DOI: 10.4251/wjgo.v17.i3.100997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/11/2024] [Accepted: 12/31/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Immunotherapy has surfaced as a promising therapeutic modality for gastric cancer (GC). A comprehensive review of advancements, current status, and research trends in GC immunotherapy is essential to inform future investigative efforts. AIM To delineate the trends, advancements, and focal points in immunotherapy for GC. METHODS We performed a bibliometric analysis of 2906 articles in English concerning GC immunotherapy published from 2000 to December 20, 2023, indexed in the Web of Science Core Collection. Data analysis and visualization were facilitated by CiteSpace (6.1.6R), VOSviewer v.1.6.17, and GraphPad Prism v8.0.2. RESULTS There has been an increase in the annual publication rate of GC immunotherapy research. China leads in publication volume, while the United States demonstrates the highest citation impact. Fudan University is notable for its citation frequency and publication output. Co-citation analysis and keyword frequency revealed and highlighted a focus on GC prognosis, the tumor microenvironment (TME), and integrative immunotherapy with targeted therapy. Emerging research areas include gastroesophageal junction cancer, adoptive immunotherapy, and the role of Treg cell in immunotherapy. CONCLUSION GC immunotherapy research is an expanding field attracting considerable scientific interest. With the clinical adoption of immunotherapy in GC, the primary goals are to enhance treatment efficacy and patient outcomes. Unlike hematological malignancies, GC's solid TME presents distinct immunological challenges that may attenuate the cytotoxic effects of immune cells on cancer cells. For instance, although CAR-T therapy is effective in hematological malignancies, it has underperformed in GC settings. Current research is centered on overcoming immunosuppression within the TME, with a focus on combinations of targeted therapy, adoptive immunotherapy, Treg cell dynamics, and precise prognosis prediction in immunotherapy. Additionally, immunotherapy's role in treating gastroesophageal junction cancer has become a novel research focus.
Collapse
Affiliation(s)
- Zhen Yuan
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jing-Hang Wang
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Hao Cui
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Shu-Yuan Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Bo Wei
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jian-Xin Cui
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| |
Collapse
|
|
4
|
Gao H, Zhang T, Li K, Li X. CD73: a new immune checkpoint for leukemia treatment. Front Immunol 2025; 16:1486868. [PMID: 40114928 PMCID: PMC11922907 DOI: 10.3389/fimmu.2025.1486868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
Recent studies on the pathogenesis of leukemia have led to remarkable advances in disease treatment. Numerous studies have shown the potential and viability of immune responses against leukemia. In the classical pathway, this process is often initiated by the upstream activity of CD39, which hydrolyzes extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to AMP. Subsequently, CD73 acts on AMP to generate adenosine, contributing to an immunosuppressive microenvironment. However, CD73 can also utilize substrates derived from other molecules through the non-canonical NAD+ pathway, specifically via the CD38/CD203a/CD73 axis, further enhancing adenosine production and facilitating immune escape. Targeting CD73 has shown potential in disrupting these immunosuppressive pathways, thereby enhancing anti-leukemic immune responses and improving patient outcomes. Inhibiting CD73 not only reduces the levels of immunosuppressive adenosine but also increases the efficacy of existing immunotherapies, such as PD-1/PD-L1 inhibitors, making it a versatile therapeutic target in leukemia treatment. This review discusses the potential of CD73 as a therapeutic target and emphasizes its unique position in the immune escape mechanism of leukemia. Moreover, this review provides an overview of the current research progress and future trends, emphasizing the clinical significance of targeting CD73 and other potential therapeutic strategies in leukemia.
Collapse
Affiliation(s)
- Huan Gao
- Marine College, Shandong University, Weihai, China
| | - Tingting Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ke Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xia Li
- Marine College, Shandong University, Weihai, China
| |
Collapse
|
|
5
|
Cho Y, Ahn S, Kim KM. PD-L1 as a Biomarker in Gastric Cancer Immunotherapy. J Gastric Cancer 2025; 25:177-191. [PMID: 39822174 PMCID: PMC11739645 DOI: 10.5230/jgc.2025.25.e4] [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: 10/31/2024] [Accepted: 11/29/2024] [Indexed: 01/19/2025] Open
Abstract
Combining chemotherapy with immune checkpoint inhibitors (ICIs) that target the programmed death-1 (PD-1) protein has been shown to be a clinically effective first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative and -positive advanced or metastatic gastric cancer (GC). Currently, PD-1 inhibitors combined with chemotherapy are the standard treatment for patients with HER2-negative/positive locally advanced or metastatic GC. Programmed death-ligand 1 (PD-L1) expression, as assessed using immunohistochemistry (IHC), is a crucial biomarker for predicting response to anti-PD-1/PD-L1 agents in various solid tumors, including GC. In GC, the PD-L1 IHC test serves as a companion or complementary diagnostic test for immunotherapy, and an accurate interpretation of PD-L1 status is essential for selecting patients who may benefit from immunotherapy. However, PD-L1 IHC testing presents several challenges that limit its reliability as a biomarker for immunotherapy. In this review, we provide an overview of the current practices of immunotherapy and PD-L1 testing in GC. In addition, we discuss the clinical challenges associated with PD-L1 testing and its future use as a biomarker for immunotherapy. Finally, we present prospective biomarkers currently under investigation as alternative predictors of immunotherapy response in GC.
Collapse
Affiliation(s)
- Yunjoo Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
6
|
Zhang X, Dai X, Liu A, Sun M, Cong L, Liang J, Liu Z, Li Z, Zhang J, Lv J, Cao F, Qu L, Liu H, Yue L, Zhai Y, Yang F, Chu J, Wang S, Xu Q, Zhou J, Nie S, Huang M, Xu R, Wang Q, Song X, Zhang D, Nan Z, Li S, Liu L. Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study. BMC Med 2024; 22:585. [PMID: 39696266 PMCID: PMC11657984 DOI: 10.1186/s12916-024-03801-5] [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: 05/09/2024] [Accepted: 11/27/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Recent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial. METHODS In this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms. RESULTS This study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1-4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high "ABC transporters" signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes. CONCLUSIONS Adding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1-4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.
Collapse
Affiliation(s)
- Xue Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- Institute of Marine Science and Technology, Shandong University, Qingdao, China
| | - Xin Dai
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- Department of Medical Oncology, Shandong Provincial Hospital of Traditional Chinese Medicine, Jinan, China
| | - Aina Liu
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Meili Sun
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University , Jinan, China
| | - Lei Cong
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University , Jinan, China
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Zimin Liu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhen Li
- Department of Oncology, Linyi Cancer Hospital, Linyi, China
| | - Jinling Zhang
- Department of Oncology, Linyi People's Hospital, Linyi, China
| | - Jing Lv
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fangli Cao
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Linli Qu
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Haiyan Liu
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Lu Yue
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Yi Zhai
- Department of Oncology, Zibo Center Hospital, Zibo, China
| | - Fujun Yang
- Department of Oncology, Weihai Municipal Hospital, Weihai, China
| | - Jiahui Chu
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuang Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Qian Xu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Jianyuan Zhou
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Shulun Nie
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Miao Huang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- Institute of Marine Science and Technology, Shandong University, Qingdao, China
| | - Ruitao Xu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Qiushi Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Xinyu Song
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Di Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Zhaodi Nan
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Song Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
| | - Lian Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
| |
Collapse
|
|
7
|
Wang J, Jiang Z, Wang K, Zheng Q, Jian J, Liu X, Chen Z, Yang R, Wang L. Construction of a necroptosis-related lncRNA signature for predicting prognosis and revealing the immune microenvironment in bladder cancer. Aging (Albany NY) 2024; 16:2812-2827. [PMID: 38319718 PMCID: PMC10911338 DOI: 10.18632/aging.205512] [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: 09/25/2023] [Accepted: 12/27/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND Bladder cancer (BCa) is a common malignancy in the urinary system. Necroptosis, a recently discovered form of programmed cell death, is closely associated with the development and progression of various types of tumors. Targeting necroptosis through anti-cancer strategies has shown potential as a therapy for cancer. We aimed to develop a necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict the survival and tumor immunity of BCa patients. METHODS We analyzed sequencing data obtained from the TCGA database, and applied least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to identify crucial NRlncRNAs for building a risk model. Using the risk score, we categorized patients into high- and low-risk groups, and assessed the accuracy with the area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves. We performed the RT-qPCR to detect the expression differences of the genes based on the risk model. RESULTS We identified a total of 296 NRlncRNAs, and 6 of them were included in the prognostic model. The AUC values for 1-, 3-, and 5-year predictions were 0.675, 0.726 and 0.734, respectively. Our risk model demonstrated excellent predictive performance and served as an independent predictor with high predictive power. Additionally, we performed PCA, TMB, GSEA analyses, and evaluated immune cell infiltration, to reveal significant differences between the high- and low-risk groups in functional signaling pathways, immunological status, and mutation profiles. Finally, we assessed the chemotherapeutic response of several drugs. According to the RT-qPCR results, we found that four NRlncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line and regulated the occurrence and progression of bladder cancer. CONCLUSION We constructed a novel NRlncRNAs-associated risk model, which could predict the prognosis and immune response of BCa patients.
Collapse
Affiliation(s)
- Jingsong Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zhengyu Jiang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Kai Wang
- Department of Urology, People’s Hospital of Hanchuan City, Xiaogan, Hubei 432300, China
| | - Qingyuan Zheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Jun Jian
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Rui Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| |
Collapse
|
|
8
|
Chen Q, Yin H, He J, Xie Y, Wang W, Xu H, Zhang L, Shi C, Yu J, Wu W, Liu L, Pu N, Lou W. Tumor Microenvironment Responsive CD8 + T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302498. [PMID: 37867243 PMCID: PMC10667825 DOI: 10.1002/advs.202302498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 08/20/2023] [Indexed: 10/24/2023]
Abstract
CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.
Collapse
Affiliation(s)
- Qiangda Chen
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Hanlin Yin
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Junyi He
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Yuqi Xie
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Wenquan Wang
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Huaxiang Xu
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Lei Zhang
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Chenye Shi
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Jun Yu
- Departments of Medicine and OncologyJohns Hopkins University School of MedicineBaltimoreMD21287USA
| | - Wenchuan Wu
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Liang Liu
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Ning Pu
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| | - Wenhui Lou
- Department of Pancreatic SurgeryCancer CenterDepartment of General SurgeryZhongshan HospitalFudan UniversityShanghai200032China
| |
Collapse
|
|
9
|
Xu X, Chen J, Li W, Feng C, Liu Q, Gao W, He M. Immunology and immunotherapy in gastric cancer. Clin Exp Med 2023; 23:3189-3204. [PMID: 37322134 DOI: 10.1007/s10238-023-01104-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/24/2023] [Indexed: 06/17/2023]
Abstract
Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. As the diagnosis of early gastric cancer is difficult, most patients are at a late stage of cancer progression when diagnosed. The current therapeutic approaches based on surgical or endoscopic resection and chemotherapy indeed improve patients' outcomes. Immunotherapy based on immune checkpoint inhibitors has opened a new era for cancer treatment, and the immune system of the host is reshaped to combat tumor cells and the strategy differs according to the patient's immune system. Thus, an in-depth understanding of the roles of various immune cells in the progression of gastric cancer is beneficial to application for immunotherapy and the discovery of new therapeutic targets. This review describes the functions of different immune cells in gastric cancer development, mainly focusing on T cells, B cells, macrophages, natural killer cells, dendritic cells, neutrophils as well as chemokines or cytokines secreted by tumor cells. And this review also discusses the latest advances in immune-related therapeutic approaches such as immune checkpoint inhibitors, CAR-T or vaccine, to reveal potential and promising strategies for gastric cancer treatment.
Collapse
Affiliation(s)
- Xiaqing Xu
- Department of Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, Henan, People's Republic of China
| | - Jiaxing Chen
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450002, Henan, People's Republic of China
| | - Wenxing Li
- Department of Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, Henan, People's Republic of China
| | - Chenlu Feng
- Department of Cancer Center, Nanyang First People's Hospital, Nanyang, 473000, Henan, People's Republic of China
| | - Qian Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450002, Henan, People's Republic of China
| | - Wenfang Gao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450002, Henan, People's Republic of China
| | - Meng He
- Department of Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, Henan, People's Republic of China.
| |
Collapse
|
|
10
|
Hou W, Zhao Y, Zhu H. Predictive Biomarkers for Immunotherapy in Gastric Cancer: Current Status and Emerging Prospects. Int J Mol Sci 2023; 24:15321. [PMID: 37895000 PMCID: PMC10607383 DOI: 10.3390/ijms242015321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Gastric cancer presents substantial management challenges, and the advent of immunotherapy has ignited renewed hope among patients. Nevertheless, a significant proportion of patients do not respond to immunotherapy, and adverse events associated with immunotherapy also occur on occasion, underscoring the imperative to identify suitable candidates for treatment. Several biomarkers, including programmed death ligand-1 expression, tumor mutation burden, mismatch repair status, Epstein-Barr Virus infection, circulating tumor DNA, and tumor-infiltrating lymphocytes, have demonstrated potential in predicting the effectiveness of immunotherapy in gastric cancer. However, the quest for the optimal predictive biomarker for gastric cancer immunotherapy remains challenging, as each biomarker carries its own limitations. Recently, multi-omics technologies have emerged as promising platforms for discovering novel biomarkers that may help in selecting gastric cancer patients likely to respond to immunotherapy. The identification of reliable predictive biomarkers for immunotherapy in gastric cancer holds the promise of enhancing patient selection and improving treatment outcomes. In this review, we aim to provide an overview of clinically established biomarkers of immunotherapy in gastric cancer. Additionally, we introduce newly reported biomarkers based on multi-omics studies in the context of gastric cancer immunotherapy, thereby contributing to the ongoing efforts to refine patient stratification and treatment strategies.
Collapse
Affiliation(s)
- Wanting Hou
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China
| | - Yaqin Zhao
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China
| | - Hong Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
| |
Collapse
|
|
11
|
Chen X, Li Y, Zhou Z, Zhang Y, Chang L, Gao X, Li Q, Luo H, Westover KD, Zhu J, Wei X. Dynamic ultrasound molecular-targeted imaging of senescence in evaluation of lapatinib resistance in HER2-positive breast cancer. Cancer Med 2023; 12:19904-19920. [PMID: 37792675 PMCID: PMC10587953 DOI: 10.1002/cam4.6607] [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: 03/24/2023] [Revised: 07/21/2023] [Accepted: 09/22/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Prolonged treatment of HER2+ breast cancer with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screen for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging to dynamically evaluate LAP resistance. METHODS AND RESULTS In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then, we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E-targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo. CONCLUSIONS Our data demonstrate that cellular senescence-based ultrasound-targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer cells, which has the potential to improve cancer treatment outcomes by altering therapeutic strategies ahead of aggressive recurrences.
Collapse
Affiliation(s)
- Xiaoyu Chen
- Department of Diagnostic and Therapeutic UltrasonographyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
- Department of UltrasoundTianjin HospitalTianjinChina
| | - Ying Li
- Breast Cancer CenterTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| | - Zhiwei Zhou
- Department of Radiation Oncology and BiochemistryUniversity of Texas Southwestern Medical CenterTexasDallasUSA
| | - Yanqiu Zhang
- Department of Diagnostic and Therapeutic UltrasonographyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| | - Luchen Chang
- Department of Diagnostic and Therapeutic UltrasonographyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| | - Xiujun Gao
- School of Biomedical Engineering and Technology, Tianjin Medical UniversityTianjinChina
| | - Qing Li
- Cancer CenterDaping Hospital, Third Military Medical UniversityChongqingChina
| | - Hao Luo
- Cancer CenterDaping Hospital, Third Military Medical UniversityChongqingChina
| | - Kenneth D. Westover
- Department of Radiation Oncology and BiochemistryUniversity of Texas Southwestern Medical CenterTexasDallasUSA
| | - Jialin Zhu
- Department of Diagnostic and Therapeutic UltrasonographyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| | - Xi Wei
- Department of Diagnostic and Therapeutic UltrasonographyTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for CancerTianjinChina
| |
Collapse
|
|
12
|
Petruk N, Siddiqui A, Tadayon S, Määttä J, Mattila PK, Jukkola A, Sandholm J, Selander KS. CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases. Front Immunol 2023; 14:1179022. [PMID: 37533856 PMCID: PMC10390692 DOI: 10.3389/fimmu.2023.1179022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/23/2023] [Indexed: 08/04/2023] Open
Abstract
Introduction Bisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known. Methods We used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody. Results Sh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups. Discussion Taken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor.
Collapse
Affiliation(s)
- Nataliia Petruk
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Arafat Siddiqui
- Institute of Biomedicine, University of Turku, Turku, Finland
- Western Cancer Centre FICAN West, Turku, Finland
| | - Sina Tadayon
- MediCity Research Laboratory, University of Turku, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Jorma Määttä
- Institute of Biomedicine, University of Turku, Turku, Finland
- Turku Center for Disease Modeling, University of Turku, Turku, Finland
| | - Pieta K. Mattila
- Institute of Biomedicine, University of Turku, Turku, Finland
- MediCity Research Laboratory, University of Turku, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Arja Jukkola
- Department of Oncology, Tampere University Hospital, Tays Cancer Center, Tampere, Finland
| | - Jouko Sandholm
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Katri S. Selander
- Department of Oncology and Radiation Therapy, Oulu University Hospital, Oulu, Finland
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
| |
Collapse
|
|
13
|
Kowash RR, Akbay EA. Tumor intrinsic and extrinsic functions of CD73 and the adenosine pathway in lung cancer. Front Immunol 2023; 14:1130358. [PMID: 37033953 PMCID: PMC10079876 DOI: 10.3389/fimmu.2023.1130358] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
The adenosine pathway is an exciting new target in the field of cancer immunotherapy. CD73 is the main producer of extracellular adenosine. Non-small cell lung cancer (NSCLC) has one of the highest CD73 expression signatures among all cancer types and the presence of common oncogenic drivers of NSCLC, such as mutant epidermal growth factor receptor (EGFR) and KRAS, correlate with increased CD73 expression. Current immune checkpoint blockade (ICB) therapies only benefit a subset of patients, and it has proved challenging to understand which patients might respond even with the current understanding of predictive biomarkers. The adenosine pathway is well known to disrupt cytotoxic function of T cells, which is currently the main target of most clinical agents. Data thus far suggests that combining ICB therapies already in the clinic with adenosine pathway inhibitors provides promise for the treatment of lung cancer. However, antigen loss or lack of good antigens limits efficacy of ICB; simultaneous activation of other cytotoxic immune cells such as natural killer (NK) cells can be explored in these tumors. Clinical trials harnessing both T and NK cell activating treatments are still in their early stages with results expected in the coming years. In this review we provide an overview of new literature on the adenosine pathway and specifically CD73. CD73 is thought of mainly for its role as an immune modulator, however recent studies have demonstrated the tumor cell intrinsic properties of CD73 are potentially as important as its role in immune suppression. We also highlight the current understanding of this pathway in lung cancer, outline ongoing studies examining therapies in combination with adenosine pathway targeting, and discuss future prospects.
Collapse
Affiliation(s)
- Ryan R Kowash
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Simmons Comprehensive Cancer Center, Dallas, TX, United States
| | - Esra A Akbay
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Simmons Comprehensive Cancer Center, Dallas, TX, United States
| |
Collapse
|
|
14
|
Sun BY, Yang ZF, Wang ZT, Liu G, Zhou C, Zhou J, Fan J, Gan W, Yi Y, Qiu SJ. Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma. World J Surg Oncol 2023; 21:90. [PMID: 36899373 PMCID: PMC9999525 DOI: 10.1186/s12957-023-02970-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND CD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC. METHODS Multi-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis. RESULTS CD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy. CONCLUSIONS High expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.
Collapse
Affiliation(s)
- Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Zhu-Tao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Gao Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Wei Gan
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| |
Collapse
|
|
15
|
Li H, Xie P, Li P, Du Y, Zhu J, Yuan Y, Wu C, Shi Y, Huang Z, Wang X, Liu D, Liu W. CD73/NT5E is a Potential Biomarker for Cancer Prognosis and Immunotherapy for Multiple Types of Cancers. Adv Biol (Weinh) 2023; 7:e2200263. [PMID: 36480312 DOI: 10.1002/adbi.202200263] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Indexed: 12/14/2022]
Abstract
Cluster of Differentiations 73 (CD73)/ecto-5'-nucleotidase (NT5E) is a novel type of immune molecular marker expressed on many tumor cells and involved in regulating the essential immune functions and affecting the prognosis of cancer patients. However, it is not clear how the NT5E is linked to the infiltration levels of the immune cells in pan-cancer patients and their final prognosis. This study explores the role of NT5E in 33 tumor types using GEPIA, TIMER, Oncomine, BioGPS databases, and several bioinformatic tools. The findings reveal that the NT5E is abnormally expressed in a majority of the types of cancers and can be used for determining the prognosis prediction ability of different cancers. Moreover, NT5E is significantly related to the infiltration status of numerous immune cells, immune-activated pathways, and immunoregulator expressions. Last, specific inhibitor molecules, like NORNICOTINE, AS-703026, and FOSTAMATINIB, which inhibit the expression of NT5E in various types of cancers, are screened with the CMap. Thus, it is proposed that NT5E can be utilized as a potential biomarker for predicting the prognosis of cancer patients and determining the infiltration of various immune cells in different types of cancers.
Collapse
Affiliation(s)
- Huisheng Li
- Department of Maxillofacial & Otorhinolaryngology Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Peng Xie
- Department of Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Ping Li
- Department of Maxillofacial & Otorhinolaryngology Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Yuheng Du
- Department of Maxillofacial & Otorhinolaryngology Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Jiajia Zhu
- Department of Maxillofacial & Otorhinolaryngology Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Yudong Yuan
- Department of Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Chao Wu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Yantao Shi
- Department of Technology, Swanshine (Tianjin) Biotechnology Development Co. Ltd, Anime East Road, Airport Economic Zone, Tianjin, 300308, China
| | - Zhiyong Huang
- Department of Industrial Biosystems and Bioprocessing Engineering, Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences, Xiqi Road Airport Economic Zone, Tianjin, 300308, China
| | - Xudong Wang
- Department of Maxillofacial & Otorhinolaryngology Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Dongying Liu
- Department of Pain Management, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Weishuai Liu
- Department of Pain Management, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| |
Collapse
|
|
16
|
Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy. Oncogene 2023; 42:1-10. [PMID: 36473909 DOI: 10.1038/s41388-022-02562-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022]
Abstract
Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.
Collapse
|
|
17
|
Zhou Y, Jiang D, Chu X, Yan M, Qi H, Wu X, Tang Y, Dai Y. High expression of CD73 contributes to poor prognosis of clear-cell renal cell carcinoma by promoting cell proliferation and migration. Transl Cancer Res 2022; 11:3634-3644. [PMID: 36388013 PMCID: PMC9641103 DOI: 10.21037/tcr-22-544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/01/2022] [Indexed: 10/12/2024]
Abstract
BACKGROUND Accumulating data have shown that high expression of CD73 is associated with poor prognosis in various cancers, however the role and significance of CD73 in clear-cell renal cell carcinoma (ccRCC) still remain unclear. The present study aims to evaluate the prognostic significance of CD73 in ccRCC and explore the potential function in vitro and in vivo. METHODS Firstly, the expression of CD73 in ccRCC was detected using clinical tissues and verified using TCGA and GEO data. Immunohistochemistry and Kaplan-Meier test were performed for survival analysis. Furthermore, knockdown or overexpression of CD73 was conducted by lentivirus transfection in ccRCC cells. MTT assay, colony formation assay, wound healing assay, transwell assay and xenograft assay were performed in vitro or in vivo. RESULTS Our results showed that CD73 was highly expressed in ccRCC, and high expression of CD73 was negatively correlated with prognosis. In addition, CD73 promoted cell proliferation and migration in vitro and in vivo. Our data also showed that CD73 played both enzymatic and non-enzymatic functions in the regulation of cell proliferation and migration in ccRCC. CONCLUSIONS These findings suggested that CD73 might promote the growth of ccRCC and contribute to poor prognosis. Taken together, CD73 may be a potential therapeutic target in ccRCC.
Collapse
Affiliation(s)
- Yihong Zhou
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Dong Jiang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Xi Chu
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Minbo Yan
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Hao Qi
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Xiang Wu
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Yuxin Tang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Yingbo Dai
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| |
Collapse
|
|
18
|
Wang J, Du L, Chen X. Adenosine signaling: Optimal target for gastric cancer immunotherapy. Front Immunol 2022; 13:1027838. [PMID: 36189223 PMCID: PMC9523428 DOI: 10.3389/fimmu.2022.1027838] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/05/2022] [Indexed: 11/21/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancy and leading cause of cancer-related deaths worldwide. Due to asymptomatic or only nonspecific early symptoms, GC patients are usually in the advanced stage at first diagnosis and miss the best opportunity of treatment. Immunotherapies, especially immune checkpoint inhibitors (ICIs), have dramatically changed the landscape of available treatment options for advanced-stage cancer patients. However, with regards to existing ICIs, the clinical benefit of monotherapy for advanced gastric cancer (AGC) is quite limited. Therefore, it is urgent to explore an optimal target for the treatment of GC. In this review, we summarize the expression profiles and prognostic value of 20 common immune checkpoint-related genes in GC from Gene Expression Profiling Interactive Analysis (GEPIA) database, and then find that the adenosinergic pathway plays an indispensable role in the occurrence and development of GC. Moreover, we discuss the pathophysiological function of adenosinergic pathway in cancers. The accumulation of extracellular adenosine inhibits the normal function of immune effector cells and facilitate the effect of immunosuppressive cells to foster GC cells proliferation and migration. Finally, we provide insights into potential clinical application of adenosinergic-targeting therapies for GC patients.
Collapse
Affiliation(s)
- Junqing Wang
- School of the 1St Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Linyong Du
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xiangjian Chen, ; Linyong Du,
| | - Xiangjian Chen
- School of the 1St Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xiangjian Chen, ; Linyong Du,
| |
Collapse
|
|
19
|
Liu H, Wu J, Xu X, Wang H, Zhang C, Yin S, He Y. Peritumoral TIGIT+CD20+ B cell infiltration indicates poor prognosis but favorable adjuvant chemotherapeutic response in gastric cancer. Int Immunopharmacol 2022; 108:108735. [DOI: 10.1016/j.intimp.2022.108735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/19/2022] [Accepted: 03/23/2022] [Indexed: 01/13/2023]
|
|
20
|
The Effects of CD73 on Gastrointestinal Cancer Progression and Treatment. JOURNAL OF ONCOLOGY 2022; 2022:4330329. [PMID: 35620732 PMCID: PMC9130010 DOI: 10.1155/2022/4330329] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/04/2022] [Indexed: 11/18/2022]
Abstract
Gastrointestinal (GI) cancer is a common and deadly malignant tumor. CD73, a cell-surface protein, acts as a switch of the adenosine-related signaling pathway that can cause significant immunosuppression. Recent evidence has emerged that CD73 is a promising immunotherapy target for regaining immune cell function and restraining tumorigenesis, and a growing stream of research indicates that combining immunotherapy with other therapies can effectively improve the prognosis and survival of GI cancer patients. Several immune checkpoint inhibitors have been approved for use in GI cancer recently; however, they have demonstrated limited efficacy. Solving the problem of immunosuppression in GI cancer is the key to developing an effective therapeutic option and the modulation of CD73 expression may provide an answer. In this review, we discuss current research on CD73 in gastric, liver, pancreatic, and colorectal cancer to evaluate its therapeutic potential as an immunotherapy target in GI cancers.
Collapse
|
|
21
|
A Novel Anti-CD73 Antibody That Selectively Inhibits Membrane CD73 Shows Antitumor Activity and Induces Tumor Immune Escape. Biomedicines 2022; 10:biomedicines10040825. [PMID: 35453575 PMCID: PMC9031174 DOI: 10.3390/biomedicines10040825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
CD73 catalyzes the conversion of ATP to adenosine, which is involved in various physiological and pathological processes, including tumor immune escape. Because CD73 expression and activity are particularly high on cancer cells and contribute to the immunosuppressive properties of the tumor environment, it is considered an attractive target molecule for specific cancer therapies. In line, several studies demonstrated that CD73 inhibition has a significant antitumor effect. However, complete blocking of CD73 activity can evoke autoimmune phenomena and adverse side effects. We developed a CD73-specific antibody, 22E6, that specifically inhibits the enzymatic activity of membrane-tethered CD73 present in high concentrations on cancer cells and cancer cell-derived extracellular vesicles but has no inhibitory effect on soluble CD73. Inhibition of CD73 on tumor cells with 22E6 resulted in multiple effects on tumor cells in vitro, including increased apoptosis and interference with chemoresistance. Intriguingly, in a xenograft mouse model of acute lymphocytic leukemia (ALL), 22E6 treatment resulted in an initial tumor growth delay in some animals, followed by a complete loss of CD73 expression on ALL cells in all 22E6 treated animals, indicating tumor immune escape. Taken together, 22E6 shows great potential for cancer therapy, favorably in combination with other drugs.
Collapse
|