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Dong D, Yu X, Liu H, Xu J, Guo J, Guo W, Li X, Wang F, Zhang D, Liu K, Sun Y. Study of immunosenescence in the occurrence and immunotherapy of gastrointestinal malignancies. Semin Cancer Biol 2025; 111:16-35. [PMID: 39929408 DOI: 10.1016/j.semcancer.2025.01.007] [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: 12/15/2024] [Revised: 01/18/2025] [Accepted: 01/26/2025] [Indexed: 02/25/2025]
Abstract
In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.
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Affiliation(s)
- Daosong Dong
- Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xue Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in the Universities of Liaoning Province, Shenyang, Liaoning 110001, China
| | - Haoran Liu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jingjing Xu
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jiayan Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Fei Wang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Dongyong Zhang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Kaiwei Liu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yanbin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
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Kim M, Je Y, Chun J, Youn YH, Park H, Nahm JH, Kim J. Helicobacter pylori Eradication Is Associated With a Reduced Risk of Metachronous Gastric Neoplasia by Restoring Immune Function in the Gastric Mucosa. Helicobacter 2025; 30:e70030. [PMID: 40169366 PMCID: PMC11961346 DOI: 10.1111/hel.70030] [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: 12/08/2024] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Helicobacter pylori infection is a significant contributing factor of gastric cancer. Metachronous neoplasms also pose a risk. The mechanism underlying the impact of H. pylori eradication on preventing metachronous gastric cancer is unclear. This study aimed to investigate immunity changes in gastric mucosa after H. pylori eradication and to identify mechanisms preventing metachronous recurrence. MATERIALS AND METHODS Patients diagnosed with gastric neoplasm and H. pylori infection, who underwent endoscopic resection, were included. Thirty-six cases of metachronous neoplasms occurring after eradication (metachronous group) were compared to 36 controls matched for age, sex, atrophy, and metaplasia (control group). Histological features and immunohistochemical staining for T-cell (CD3, CD4, and CD8) and immune exhaustion (forkhead/winged helix transcription factor and programmed cell death-ligand 1) markers in the non-tumor-bearing mucosa were evaluated. RESULTS In histologic features, glandular atrophy and intestinal metaplasia in the gastric mucosa significantly improved following H. pylori eradication in the control group (p < 0.001, 0.008), whereas they did not improve in the metachronous group (p = 0.449, 0.609). CD8 and CD8/CD3 ratios increased in the control group (p < 0.001, 0.04), but did not show differences in the metachronous group (p = 0.057, 0.245). The CD4/CD3 ratio and programmed cell death-ligand 1/CD4 expression significantly decreased after H. pylori eradication in the control group (p = 0.003, 0.042), but not in the metachronous group (p = 0.54, 0.55). CONCLUSIONS This observational study suggests that H. pylori eradication may prevent the recurrence of gastric neoplasia by improving histological inflammation and overcoming immune exhaustion.
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Affiliation(s)
- Min‐Jae Kim
- Department of Internal Medicine, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
| | - Yeonjin Je
- Graduate School of MedicineYonsei UniversitySeoulKorea
| | - Jaeyoung Chun
- Department of Internal Medicine, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
| | - Young Hoon Youn
- Department of Internal Medicine, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
| | - Hyojin Park
- Department of Internal Medicine, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
| | - Ji Hae Nahm
- Department of Pathology, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
| | - Jie‐Hyun Kim
- Department of Internal Medicine, Gangnam Severance HospitalYonsei University College of MedicineSeoulKorea
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Yu ZH, Ma WQ, Ren JW, Zhang XT, Chu L. Role of Computed Tomography in Predicting Programmed Death Ligand-1 Positivity in Gastric Adenocarcinoma. J Multidiscip Healthc 2025; 18:609-621. [PMID: 39935434 PMCID: PMC11812451 DOI: 10.2147/jmdh.s495962] [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: 11/18/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Objective To examine the association between computed tomography (CT) imaging characteristics and programmed death ligand-1 (PD-L1) expression in patients with gastric adenocarcinoma (GAC), and to develop a nomogram model for prediction. Methods The patients were randomly allocated into a training set and a validation set at a ratio of 7:3. The training set was further divided into a PD-L1 positive group and a PD-L1 negative group, based on the combined positive score (CPS). Univariate and multivariate logistic regression analyses were performed to identify independent predictors of PD-L1 positivity. A nomogram was developed to assess the model's predictive performance, which was evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). It was also compared with the model established by previous study. Results Patients with PD-L1-positive gastric adenocarcinoma exhibited a higher prevalence of larger short diameters of lymph nodes (LNs) (≥ 1 cm), and lower CT attenuation values in the venous and delayed phases compared to those in the PD-L1-negative group. Short diameter of LNs, and CT attenuation values in the delayed phase were identified as independent predictors of PD-L1 positivity. The nomogram analysis indicated that CT attenuation values in the delayed phase were the most significant predictor of PD-L1 positivity, followed by short diameter of LNs. Conclusion The GAC prediction model based on the CT imaging features is effective in predicting PD-L1 expression levels and demonstrates strong clinical applicability.
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Affiliation(s)
- Zhi-Hong Yu
- Department of Ultrasound, Shanxi Provincial People’s Hospital, The Fifth Hospital of Shanxi Medical University, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, 030012, People’s Republic of China
| | - Wei-Qin Ma
- Department of CT/MRI, Lvliang People’s Hospital, Shanxi Province, Lvliang, Shanxi, 033000, People’s Republic of China
| | - Ji-Wei Ren
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Xu-Ting Zhang
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Lin Chu
- Department of Radiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China
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Cozac-Szőke AR, Cozac DA, Negovan A, Tinca AC, Vilaia A, Cocuz IG, Sabău AH, Niculescu R, Chiorean DM, Tomuț AN, Cotoi OS. Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer. Int J Mol Sci 2025; 26:1156. [PMID: 39940924 PMCID: PMC11818890 DOI: 10.3390/ijms26031156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Gastric cancer (GC) ranks as the fifth most prevalent malignant neoplasm globally, with an increased death rate despite recent advancements in research and therapeutic options. Different molecular subtypes of GC have distinct interactions with the immune system, impacting the tumor microenvironment (TME), prognosis, and reaction to immunotherapy. Tumor-infiltrating lymphocytes (TILs) in the TME are crucial for preventing tumor growth and metastasis, as evidenced by research showing that patients with GC who have a significant density of TILs have better survival rates. But cancer cells have evolved a variety of mechanisms to evade immune surveillance, both sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) and Programmed Death-Ligand 1 (PD-L1) playing a pivotal role in the development of an immunosuppressive TME. They prevent T cell activation and proliferation resulting in a decrease in the immune system's capacity to recognize and eliminate malignant cells. These immune checkpoint molecules function via different but complementary mechanisms, the expression of Siglec-15 being mutually exclusive with PD-L1 and, therefore, providing a different therapeutic approach. The review explores how TILs affect tumor growth and patient outcomes in GC, with particular emphasis on their interactions within the TME and potential targeting of the PD-L1 and Siglec-15 pathways for immunotherapy.
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Affiliation(s)
- Andreea-Raluca Cozac-Szőke
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Dan Alexandru Cozac
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Emergency Institute for Cardiovascular Diseases and Transplantation Targu Mures, 540142 Targu Mures, Romania
| | - Anca Negovan
- Department of Clinical Science-Internal Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania;
| | - Andreea Cătălina Tinca
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Alexandra Vilaia
- Department of Infectious Diseases I, Doctoral School of Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Iuliu-Gabriel Cocuz
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Adrian Horațiu Sabău
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Raluca Niculescu
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Diana Maria Chiorean
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Alexandru Nicușor Tomuț
- Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania;
| | - Ovidiu Simion Cotoi
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
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Chen H, Zheng Q, Jiang Y, Lin L, Yang Y. IDO1 Expression and CD8+ T-Cell Levels Are Useful Prognostic Biomarkers in Preoperative Gastric Cancer Specimens Before Neoadjuvant Chemotherapy. Appl Immunohistochem Mol Morphol 2025; 33:1-9. [PMID: 39636312 DOI: 10.1097/pai.0000000000001238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 06/05/2024] [Indexed: 12/07/2024]
Abstract
The tumor immune microenvironment occupies an important position in gastric cancer. In this study, we investigated the relationship between indoleamine 2,3-dioxygenase 1 (IDO1), programmed cell death 1 ligand (PD-L1) expressioon, and CD8+ T-cell levels and their efficacy and prognostic value in preoperative gastric cancer specimens before neoadjuvant chemotherapy (NAC). A total of 162 patients with locally advanced gastric cancer were collected in this study. IDO1, PD-L1 expression, and CD8+ T-cell levels in the biopsy samples was detected by immunohistochemical staining, and the relationship between these indexes and the patients' clinicopathological parameters, chemotherapeutic efficacy, and prognosis were investigated. The IDO1 positivity rate was 43.2%. High expression of IDO1 was significantly associated with poor chemotherapeutic efficacy, lymph node metastasis (P<0.05). The PD-L1 positivity rate (using the combined positive score) was 38.2%, and was not related to any clinicopathological variable. Higher CD8+ T-cell levels were associated with a lower rate of lymph node metastasis and lower ypTNM stage (P<0.05). Higher CD8+ T-cell levels were negatively correlated with IDO1 expression (r=-0.224, P<0.05) and positively correlated with PD-L1 expression (r=0.254, P<0.05). Cox regression analysis demonstrated that higher CD8+ T-cell levels was an independent risk factor for overall survival (OS) and the expression of IDO1 had a significantly poorer disease-free survival (DFS). Overexpression of IDO1 and lower CD8+ T-cell levels were associated with poor survival in patients with gastric cancer who received neoadjuvant chemotherapy, and overexpression of IDO1 were associated with the poor tumor response. Our data suggest that IDO1 and CD8 testing of biopsy specimens might be a simple and effective prognostic biomarker for gastric cancer, and IDO1 could predict efficacy of neoadjuvant chemotherapy in gastric cancer.
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Affiliation(s)
- Hu Chen
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - QiaoLin Zheng
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yiting Jiang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yinghong Yang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
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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.
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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
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Sewastjanow-Silva M, Kwiatkowski E, Yamashita K, Abdelhakeem A, Yoshimura K, Vicentini ER, Pizzi MP, Jin J, Fan Y, Zou G, Wang L, Yin F, Dhar SS, Blum Murphy M, Mares JE, Li JJ, Gan Q, Waters RE, Rogers JE, Ajani JA. Three biomarkers (HER2, PD-L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience. Int J Cancer 2024; 155:2277-2286. [PMID: 38995150 DOI: 10.1002/ijc.35090] [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: 01/16/2024] [Revised: 05/11/2024] [Accepted: 06/14/2024] [Indexed: 07/13/2024]
Abstract
Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.
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Affiliation(s)
- Matheus Sewastjanow-Silva
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Evan Kwiatkowski
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kohei Yamashita
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ahmed Abdelhakeem
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Katsuhiro Yoshimura
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ernesto R Vicentini
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Melissa P Pizzi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jiankang Jin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gengyi Zou
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lingzhi Wang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Feng Yin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shilpa S Dhar
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mariela Blum Murphy
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeannette E Mares
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jenny J Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Qiong Gan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Rebecca E Waters
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jane E Rogers
- Department of Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Esfahani SA, Ma L, Krishna S, Ma H, Raheem SJ, Shuvaev S, Rotile NJ, Weigand-Whittier J, Boice AT, Borges N, Treaba CA, Deffler C, Diyabalanage H, Humblet V, Sosnovik DE, Mahmood U, Heidari P, Shih A, Catana C, Strickland MR, Klempner SJ, Caravan P. Development of a fibrin-targeted theranostic for gastric cancer. Sci Transl Med 2024; 16:eadn7218. [PMID: 39661705 DOI: 10.1126/scitranslmed.adn7218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 08/18/2024] [Accepted: 11/20/2024] [Indexed: 12/13/2024]
Abstract
Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human 64Cu-FBP8 fibrin-targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary (n = 7) and 11.2 ± 6.6 in metastatic (n = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 (64Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that 90Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of 90Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of 90Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.
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Affiliation(s)
- Shadi A Esfahani
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Li Ma
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Shriya Krishna
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Hua Ma
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Shvan J Raheem
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Sergey Shuvaev
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Nicholas J Rotile
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Jonah Weigand-Whittier
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Avery T Boice
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Nicholas Borges
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Constantina A Treaba
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Caitlin Deffler
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | | | | | - David E Sosnovik
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Umar Mahmood
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Pedram Heidari
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Angela Shih
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ciprian Catana
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Matthew R Strickland
- Division of Hematology-Oncology, Mass General Cancer Center and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Samuel J Klempner
- Division of Hematology-Oncology, Mass General Cancer Center and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Peter Caravan
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Institute for Innovation in Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
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9
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Li N, Li Y, Li J, Tang S, Gao H, Li Y. Correlation of the abundance of MDSCs, Tregs, PD-1, and PD-L1 with the efficacy of chemotherapy and prognosis in gastric cancer. Lab Med 2024:lmae090. [PMID: 39566022 DOI: 10.1093/labmed/lmae090] [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: 11/22/2024] Open
Abstract
OBJECTIVE The aim of this study was to investigate the relationship between tumor microenvironment markers (myeloid-derived suppressor cells [MDSCs], regulatory T cells [Tregs], programmed cell death 1 [PD-1], and programmed death ligand 1 [PD-L1]) and chemotherapy efficacy and prognosis in advanced gastric cancer, identifying potential monitoring indicators. METHODS Advanced gastric cancer patients' MDSC and Treg expression was measured by flow cytometry pre- and postchemotherapy; PD-1 and PD-L1 expression in cancer tissues was assessed by immunohistochemistry. Correlations with chemotherapy outcomes and prognosis were analyzed. RESULTS Postchemotherapy reductions in MDSC and Treg levels correlated with chemotherapy efficacy (P <.01). Negative PD-1 and PD-L1 expression in cancer tissues predicted better chemotherapy responses (P <.01). Patients with lower MDSC and Treg levels and negative PD-1 and PD-L1 had significantly longer median progression-free survival (PFS) and overall survival (OS) (P <.05). CONCLUSION In advanced gastric cancer, reduced peripheral blood MDSC and Treg levels postchemotherapy and negative PD-1 and PD-L1 expression in tissues are associated with improved chemotherapy efficacy and are independent prognostic factors for PFS and OS.
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Affiliation(s)
- Na Li
- Cancer Center of Suining Central Hospital, Suining 629000, China
- Department of Medical Oncology, First Affiliated Hospital of Medical College of Shihezi University, Shihezi 832000, China
| | - Yun Li
- Radionuclide Diagnosis and Treatment Center, Beijing Nuclear Industry Hospital, Beijing 102413, China
| | - Jing Li
- Department of Medical Oncology, First Affiliated Hospital of Medical College of Shihezi University, Shihezi 832000, China
| | - Shimin Tang
- Cancer Center of Suining Central Hospital, Suining 629000, China
| | - Hongbo Gao
- Radionuclide Diagnosis and Treatment Center, Beijing Nuclear Industry Hospital, Beijing 102413, China
| | - Yong Li
- Department of Radiology, Suining Central Hospital, Suining 629000, China
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10
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Shaibu Z, Yang F, Ting L, Dzidula L, Yusuf AE, Chen ZH, Zhu W. Comparative efficacy of programmed death ligand 1 inhibition and chemotherapy in advanced gastric or gastroesophageal junction cancer with combined positive score - a meta-analysis. Contemp Oncol (Pozn) 2024; 28:183-190. [PMID: 39512538 PMCID: PMC11538983 DOI: 10.5114/wo.2024.144107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 09/24/2024] [Indexed: 11/15/2024] Open
Abstract
Advanced gastric and gastroesophageal junction cancer (G/GEJC) poses significant therapeutic challenges. Immune checkpoint inhibitors, particularly targeting programmed cell death ligand-1 (PD-L1), have emerged as promising agents to enhance patient outcomes. This meta-analysis evaluates the efficacy of PD-L1 inhibitors compared to chemotherapy in patients with advanced G/GEJC characterised by varying combined positive scores (CPS). We systematically searched PubMed, Google Scholar, and Web of science for clinical trial studies comparing PD-L1 inhibitors and chemotherapy in CPS-positive patients, focusing on studies published up to 10 April 2023. Studies were evaluated with risk of bias tools. The primary clinical endpoint analysed in this study was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). This study is registered with Prospero (CRD42023495607). A total of 10 studies comprising 4522 participants were included. Our analysis revealed no statistically significant difference in CPS values between PD-L1 inhibitors and chemotherapy groups (≥ 1 : 1.03 [95% CI: 0.86-1.24], ≤ 1 : 0.92 [95% CI: 0.77-1.11]). However, the pooled hazard ratio for OS favoured PD-L1 inhibitors (hazard ratios - HR, 0.83, [95% CI: 0.78-0.88] and p < 0.00001), while PFS was better after chemotherapy (HR 1.28, [95% CI: 1.04-1.58], p = 0.02). Program death ligand-1 inhibitors improve OS, while chemotherapy enhances PFS in advanced G/GEJC, warranting further investigation into the impact of CPS on treatment outcomes.
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Affiliation(s)
- Zakari Shaibu
- Department of Gastrointestinal Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002 Jiangsu, People’s Republic of China
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fumeng Yang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Liu Ting
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lily Dzidula
- Claremont Graduate University, School of Community and Global Health, Claremont, USA
| | - Amina Elmi Yusuf
- Department of Emergency Medicine, Second Affiliated Hospital of Nanjing Medical University, China
| | - Zhi-hong Chen
- Department of Gastrointestinal Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002 Jiangsu, People’s Republic of China
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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11
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Kuwata T. Molecular classification and intratumoral heterogeneity of gastric adenocarcinoma. Pathol Int 2024; 74:301-316. [PMID: 38651937 PMCID: PMC11551831 DOI: 10.1111/pin.13427] [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: 01/21/2024] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/25/2024]
Abstract
Gastric cancers frequently harbor striking histological complexity and diversity between lesions as well as within single lesions, known as inter- and intratumoral heterogeneity, respectively. The latest World Health Organization Classification of Tumors designated more than 30 histological subtypes for gastric epithelial tumors, assigning 12 subtypes for gastric adenocarcinoma (GAD). Meanwhile, recent advances in genome-wide analyses have provided molecular aspects to the histological classification of GAD, and consequently revealed different molecular traits underlying these histological subtypes. Moreover, accumulating knowledge of comprehensive molecular profiles has led to establishing molecular classifications of GAD, which are often associated with clinical biomarkers for therapeutics and prognosis. However, most of our knowledge of GAD molecular profiles is based on inter-tumoral heterogeneity, and the molecular profiles underlying intratumoral heterogeneity are yet to be determined. In this review, recently established molecular classifications of GAD are introduced in the aspect of pathological diagnosis and are discussed in the context of intratumoral heterogeneity.
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Affiliation(s)
- Takeshi Kuwata
- Department of Genetic Medicine and ServicesNational Cancer Center Hospital EastKashiwaChibaJapan
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12
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Han Z, Wang N, Qiao Q, He X, Wang N. Association of PD-L1 Expression with Clinicopathologic Characters in Gastric Cancer: A Comprehensive Meta-analysis. Curr Med Chem 2024; 31:3198-3216. [PMID: 37921182 DOI: 10.2174/0109298673263784230922060257] [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: 05/24/2023] [Revised: 07/18/2023] [Accepted: 08/16/2023] [Indexed: 11/04/2023]
Abstract
PURPOSE The expression level of programmed death ligand-1(PD-L1) in patients with gastric cancer is the key to determining the use of immune drugs. The relationship between PD-L1 expression level and clinical characteristics is worth exploring. METHODS By setting the search terms correlated to PD-L1 and gastric cancer, a nearly comprehensive search was carried out in four major databases, and the deadline for searching was September 1, 2022. The retrieved documents were further screened by strict inclusion and exclusion criteria after removing the duplication. Next, the quality of the included studies was evaluated with the Newcastle-Ottawa Scale (NOS) scale. Finally, the STATA15.1 software was used to process data and draw plots, and the odds ratios (ORs) were adopted to assess the pooled effect size. RESULTS A total of 85 works of literature were included in this study through screening strictly, and detailed data were extracted after evaluating the quality of the literature. The process of analysis was conducted in the whole population, Asia-Africa population, European and American population, and Asian population with CPS≥1, amd all found that the expression of PD-L1 in gastric cancer was correlated with age, tumor size, EBV infection, Her-2 expression and microsatellite status. However, the subgroup of the region also found some differences in Asian and Western regions, which was interesting and worth studying further. The included research of this study did not have significant publish bias. CONCLUSION After careful analysis, this study found that age (>60 years), tumor size (>5cm), EBV infection (+), Her-2 expression (+), microsatellite status (MSI), and mismatch repair status (dMMR) were risk factors for positive expression of PD-L1 in gastric cancer.
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Affiliation(s)
- Zhuo Han
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
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13
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Zou Y, Wang J, Zhang J, Guo Q, Song Z, Tang H. Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer. Oncol Lett 2024; 27:20. [PMID: 38058467 PMCID: PMC10696633 DOI: 10.3892/ol.2023.14153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/11/2023] [Indexed: 12/08/2023] Open
Abstract
The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.
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Affiliation(s)
- Yunlian Zou
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Jinli Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Jinping Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Qiang Guo
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Zhengji Song
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Hui Tang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
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14
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Wang J, Deng R, Chen S, Deng S, Hu Q, Xu B, Li J, He Z, Peng M, Lei S, Ma T, Chen Z, Zhu H, Zuo C. Helicobacter pylori CagA promotes immune evasion of gastric cancer by upregulating PD-L1 level in exosomes. iScience 2023; 26:108414. [PMID: 38047083 PMCID: PMC10692710 DOI: 10.1016/j.isci.2023.108414] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/01/2023] [Accepted: 11/02/2023] [Indexed: 12/05/2023] Open
Abstract
Cytotoxin-associated gene A (CagA) of Helicobacter pylori (Hp) may promote immune evasion of Hp-infected gastric cancer (GC), but potential mechanisms are still under explored. In this study, the positive rates of CagA and PD-L1 protein in tumor tissues and the high level of exosomal PD-L1 protein in plasma exosomes were significantly associated with the elevated stages of tumor node metastasis (TNM) in Hp-infected GC. Moreover, the positive rate of CagA was positively correlated with the positive rate of PD-L1 in tumor tissues and the level of PD-L1 protein in plasma exosomes, and high level of exosomal PD-L1 might indicate poor prognosis of Hp-infected GC. Mechanically, CagA increased PD-L1 level in exosomes derived from GC cells by inhibiting p53 and miRNA-34a, suppressing proliferation and anticancer effect of CD8+ T cells. This study provides sights for understanding immune evasion mediated by PD-L1. Targeting CagA and exosomal PD-L1 may improve immunotherapy efficacy of Hp-infected GC.
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Affiliation(s)
- Jinfeng Wang
- Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China
| | - Rilin Deng
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China
| | - Shuai Chen
- School of Integrated Traditional Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, Hunan, China
| | - Shun Deng
- Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China
| | - Qi Hu
- Graduates School, University of South China, Hengyang 421001, Hunan, China
| | - Biaoming Xu
- Graduates School, University of South China, Hengyang 421001, Hunan, China
| | - Junjun Li
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Zhuo He
- Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China
| | - Mingjing Peng
- Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China
| | - Sanlin Lei
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Tiexiang Ma
- The Third Department of General Surgery, The Central Hospital of Xiangtan City, Xiangtan 411100, Hunan, China
| | - Zhuo Chen
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, Hunan, China
| | - Haizhen Zhu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China
| | - Chaohui Zuo
- Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China
- School of Integrated Traditional Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, Hunan, China
- Graduates School, University of South China, Hengyang 421001, Hunan, China
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15
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Chivu-Economescu M, Herlea V, Dima S, Sorop A, Pechianu C, Procop A, Kitahara S, Necula L, Matei L, Dragu D, Neagu AI, Bleotu C, Diaconu CC, Popescu I, Duda DG. Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients. Gastric Cancer 2023; 26:934-946. [PMID: 37668884 DOI: 10.1007/s10120-023-01429-7] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/28/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND In this study, we compared programmed death-ligand 1 (PD-L1) expression in primary tissue samples and its soluble form (sPD-L1) concentration in matched preoperative plasma samples from gastric cancer patients to understand the relationship between tissue and plasma PD-L1 expression and to determine its diagnostic and prognostic value. METHODS PD-L1 expression in tissue was assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), and sPD-L1 concentration in plasma was quantified by ELISA. The levels of the CD274 gene, which encodes for PD-L1 protein, were examined as part of bulk tissue RNA-sequencing analyses. Additionally, we evaluated the association between sPD-L1 levels and various laboratory parameters, disease characteristics, and patient outcomes. RESULTS GC patients had significantly higher levels of sPD-L1 in their plasma (71.69 pg/mL) compared to healthy controls (35.34 pg/mL) (p < 0.0001). Moreover, sPD-L1 levels were significantly correlated with tissue PD-L1 protein, CD274 mRNA expression, larger tumor size, advanced tumor stage, and lymph node metastasis. Elevated sPD-L1 levels (> 103.5 ng/mL) were associated with poor overall survival (HR = 2.16, 95%CI 1.15-4.08, p = 0.017). Furthermore, intratumoral neutrophil and dendritic cell levels were directly correlated with plasma sPD-L1 concentration in the GC patients. CONCLUSIONS sPD-L1 was readily measurable in GC patients, and its level was associated with GC tissue PD-L1 expression, greater inflammatory cell infiltration, disease progression, and survival. Thus, sPD-L1 may be a useful minimally invasive diagnostic and prognostic biomarker in GC patients.
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, 022328, Bucharest, Romania
| | - Simona Dima
- Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328, Bucharest, Romania
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328, Bucharest, Romania
- Carol Davila University of Medicine and Pharmacy, 050474, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328, Bucharest, Romania
| | - Catalin Pechianu
- Department of Pathology, Fundeni Clinical Institute, 022328, Bucharest, Romania
| | - Alexandru Procop
- Department of Pathology, Fundeni Clinical Institute, 022328, Bucharest, Romania
| | - Shuji Kitahara
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Cox-724, 100 Blossom St., Boston, MA, 02114, USA
| | - Laura Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Denisa Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Ana-Iulia Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania
| | - Irinel Popescu
- Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328, Bucharest, Romania
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328, Bucharest, Romania
| | - Dan G Duda
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Cox-724, 100 Blossom St., Boston, MA, 02114, USA.
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16
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Liu L, Niu L, Zheng X, Xiao F, Sun H, Deng W, Cai J. PD-L1 expression-related PI3K pathway correlates with immunotherapy efficacy in gastric cancer. Ther Adv Med Oncol 2023; 15:17588359231205853. [PMID: 37868079 PMCID: PMC10586003 DOI: 10.1177/17588359231205853] [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: 04/13/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
Background The programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy. Methods PD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases. Results Positive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy. Conclusion This study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.
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Affiliation(s)
- Langbiao Liu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lei Niu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xue Zheng
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Fei Xiao
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Huaibo Sun
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Wei Deng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Xicheng District, Beijing 100050,China
| | - Jun Cai
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Xicheng District, Beijing, 100050, China
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17
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Zhou Z, An R, You L, Liang K, Wang X. Banxia Xiexin decoction: A review on phytochemical, pharmacological, clinical and pharmacokinetic investigations. Medicine (Baltimore) 2023; 102:e34891. [PMID: 37657053 PMCID: PMC10476818 DOI: 10.1097/md.0000000000034891] [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: 03/27/2023] [Accepted: 08/02/2023] [Indexed: 09/03/2023] Open
Abstract
Banxia Xiexin decoction (BXD), a famous traditional Chinese prescription constituted by Pinelliae Rhizoma, Zingiberis Rhizoma, Scutellariae Radix, Coptidis Rhizoma, Ginseng Radix et Rhizoma, Jujubae Fructus and Glycyrrhizae Radix et Rhizoma Praeparata Cum Mell, has notable characteristics of acrid-opening, bitter down-bearing and sweet-tonification, interfering with tumors, gastrointestinal diseases, central nervous system diseases and much more. Based on the wide clinical applications, current investigations of BXD focused on several aspects: chemical analysis to explore the underlying substrates responsible for the therapeutic effects; basic studies on pharmacological actions of the whole prescription or of those representative ingredients to demonstrate the intriguing molecular targets for specific pathological processes; pharmacokinetic feature studies of single or all components of BXD to reveal the chemical basis and synergistic actions contributing to the pharmacological and clinically therapeutic effects. In this review, we summarized the main achievements of phytochemical, pharmacological, clinical and pharmacokinetic profiles of BXD and its herbal or pharmacologically active chemicals, as well as discussions of our understanding which further reveals the significance of BXD clinically.
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Affiliation(s)
- Zehua Zhou
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rui An
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lisha You
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kun Liang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinhong Wang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
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18
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Chen XJ, Wei CZ, Lin J, Zhang RP, Chen GM, Li YF, Nie RC, Chen YM. Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis. Biomedicines 2023; 11:2003. [PMID: 37509642 PMCID: PMC10377298 DOI: 10.3390/biomedicines11072003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/07/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. METHODS Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. RESULTS In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. CONCLUSIONS Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis.
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Affiliation(s)
- Xiao-Jiang Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Cheng-Zhi Wei
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Jun Lin
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Ruo-Peng Zhang
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Guo-Ming Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Yuan-Fang Li
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Run-Cong Nie
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
| | - Yong-Ming Chen
- State Key Laboratory of Oncology in South China, Department of Gastric Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou 510060, China
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19
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Yang WJ, Zhao HP, Yu Y, Wang JH, Guo L, Liu JY, Pu J, Lv J. Updates on global epidemiology, risk and prognostic factors of gastric cancer. World J Gastroenterol 2023; 29:2452-2468. [PMID: 37179585 PMCID: PMC10167900 DOI: 10.3748/wjg.v29.i16.2452] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/19/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023] Open
Abstract
Gastric cancer (GC) is defined as the primary epithelial malignancy derived from the stomach, and it is a complicated and heterogeneous disease with multiple risk factors. Despite its overall declining trend of incidence and mortality in various countries over the past few decades, GC remains the fifth most common malignancy and the fourth leading cause of cancer-related death globally. Although the global burden of GC has shown a significant downward trend, it remains severe in certain areas, such as Asia. GC ranks third in incidence and mortality among all cancer types in China, and it accounts for nearly 44.0% and 48.6% of new GC cases and GC-related deaths in the world, respectively. The regional differences in GC incidence and mortality are obvious, and annual new cases and deaths are increasing rapidly in some developing regions. Therefore, early preventive and screening strategies for GC are urgently needed. The clinical efficacies of conventional treatments for GC are limited, and the developing understanding of GC pathogenesis has increased the demand for new therapeutic regimens, including immune checkpoint inhibitors, cell immunotherapy and cancer vaccines. The present review describes the epidemiology of GC worldwide, especially in China, summarizes its risk and prognostic factors, and focuses on novel immunotherapies to develop therapeutic strategies for the management of GC patients.
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Affiliation(s)
- Wen-Juan Yang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Jun-Ye Liu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Jie Pu
- Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
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20
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Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer. Gastric Cancer 2023; 26:393-404. [PMID: 36781556 PMCID: PMC10115710 DOI: 10.1007/s10120-023-01364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 01/11/2023] [Indexed: 02/15/2023]
Abstract
BACKGROUND We evaluated the relevance of PD-1+CD8+ T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME). METHODS Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs. RESULTS In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B+] (r = 0.714, p < 0.001) and proliferative [Ki-67+] (r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1high compared to CD8PD-1low tumors. CONCLUSION This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1+CD8+ T-cells being associated with improved OS. CD8PD-1high tumors have distinct features of an immunologically active, T-cell inflamed TME.
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21
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Si L, Pan X, He K, Sun L, Wang Y, Xu X, Lu J. PD‐L1
expression by different scoring methods and different cutoff values and correlation with clinicopathological characteristics in gastric cancer: A retrospective study. PRECISION MEDICAL SCIENCES 2023. [DOI: 10.1002/prm2.12094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Lixiang Si
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - XiaoHua Pan
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Kang He
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Ling Sun
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Yajing Wang
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Xinyu Xu
- The Department of Pathology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Jianwei Lu
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
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22
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Tumor immunology. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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23
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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24
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Mansorunov D, Apanovich N, Kipkeeva F, Nikulin M, Malikhova O, Stilidi I, Karpukhin A. The Correlation of Ten Immune Checkpoint Gene Expressions and Their Association with Gastric Cancer Development. Int J Mol Sci 2022; 23:ijms232213846. [PMID: 36430322 PMCID: PMC9695628 DOI: 10.3390/ijms232213846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors.
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Affiliation(s)
- Danzan Mansorunov
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Natalya Apanovich
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Fatimat Kipkeeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
| | - Maxim Nikulin
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Olga Malikhova
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Ivan Stilidi
- Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, 115478 Moscow, Russia
| | - Alexander Karpukhin
- Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia
- Correspondence: ; Tel.: +7-499-324-12-39
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Sewastjanow-Silva M, Yamashita K, Rosa Vicentini E, Hirschmann M, Pool Pizzi M, Trail AM, Waters RE, Rogers JE, Ajani JA. Nivolumab with or without chemotherapy for metastatic gastroesophageal cancers and future perspectives. Expert Rev Anticancer Ther 2022; 22:1177-1181. [PMID: 36266061 DOI: 10.1080/14737140.2022.2139241] [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: 01/12/2023]
Abstract
INTRODUCTION Gastroesophageal cancers (GEC) are frequently found at the advanced stage. GEC treatment advancements have been limited and prognosis, therefore, remains poor. Through numerous clinical trials, the addition of immune checkpoint inhibitors, including nivolumab, to conventional therapy has demonstrated a survival benefit. AREAS COVERED Here, we focus on the function of nivolumab in patients with advanced GECs. We discuss the most recent trials that led to nivolumab's incorporation into therapy and pathways forward. EXPERT OPINION Nivolumab in combination with chemotherapy appears well tolerated, with only a small number of patients reporting severe toxicity; therefore, it may be possible to add additional biological agents to improve outcomes. A number of 'nivolumab plus other agents' is currently being investigated, and we anticipate continued advancement in GEC management in the coming years.
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Affiliation(s)
- Matheus Sewastjanow-Silva
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Kohei Yamashita
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Ernesto Rosa Vicentini
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Meita Hirschmann
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Melissa Pool Pizzi
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Allison Michelle Trail
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Rebecca E Waters
- Departments of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Jane E Rogers
- Departments of Pharmacy Clinical Programs, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Departments of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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Lian J, Zhang G, Zhang Y, Liu H, Zhang J, Nan P, Tian W. PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance. Dig Liver Dis 2022; 54:1419-1427. [PMID: 35123909 DOI: 10.1016/j.dld.2022.01.128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 01/10/2022] [Accepted: 01/16/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND The upregulation of programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor 2 (HER2) may play a role in gastric adenocarcinoma (GAC). AIM To study PD-L1 and HER-2 expression and prognosis in GAC. METHODS PD-L1 and HER2 expression was determined in tumor tissues of 75 patients with GAC. The correlations between PD-L1, HER2 expression, and clinicopathological factors were analyzed. RESULTS The positive expression rate for PD-L1 was 57.3% (43/75) and the HER2 over-expression rate was 17.3% (13/75). PD-L1 expression negatively correlated with the grade of GAC differentiation (r =-0.26, P<0.05). Approximately 85% of HER2-positive GACs were found to be PD-L1-positive and PD-L1 expression positively correlated with HER2 overexpression. The TNM stage and combined HER2 and PD-L1 expression were independent prognostic factors affecting the survival of patients with GAC. The median overall survival and recurrence-free survival of groups I (HER2 overexpression and PD-L1 positive), II (HER2 overexpression and PD-L1 negative), III (No HER2 overexpression and PD-L1 positive) and IV (No HER2 overexpression and PD-L1 negative) were (47 (17-77), 15 (0-44), 81 (62-101), and 78 (60-98) months, respectively. CONCLUSION PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.
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Affiliation(s)
- Jie Lian
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Guanjun Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China.
| | - Yun Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Heng Liu
- Department of Radiology, Affiliated Hospital of Zunyi Medical University, Medical Imaging Center of Guizhou Province, Zunyi, Guizhou 563003, P.R. China
| | - Jiaojiao Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Pengfei Nan
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Wei Tian
- Department of Pathology, No. 215 Hospital of Shanxi Nuclear Industry, Xianyang 712000, China
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27
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Kudo-Saito C, Boku N, Hirano H, Shoji H. Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer. Front Immunol 2022; 13:1009701. [PMID: 36211375 PMCID: PMC9539086 DOI: 10.3389/fimmu.2022.1009701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/13/2022] [Indexed: 12/03/2022] Open
Abstract
Despite the clinical outcomes being extremely limited, blocking immune inhibitory checkpoint pathways has been in the spotlight as a promising strategy for treating gastrointestinal cancer. However, a distinct strategy for the successful treatment is obviously needed in the clinical settings. Myeloid cells, such as neutrophils, macrophages, dendritic cells, and mast cells, are the majority of cellular components in the human immune system, but have received relatively less attention for the practical implementation than T cells and NK cells in cancer therapy because of concentration of the interest in development of the immune checkpoint blocking antibody inhibitors (ICIs). Abnormality of myeloid cells must impact on the entire host, including immune responses, stromagenesis, and cancer cells, leading to refractory cancer. This implies that elimination and reprogramming of the tumor-supportive myeloid villains may be a breakthrough to efficiently induce potent anti-tumor immunity in cancer patients. In this review, we provide an overview of current situation of the IC-blocking therapy of gastrointestinal cancer, including gastric, colorectal, and esophageal cancers. Also, we highlight the possible oncoimmunological components involved in the mechanisms underlying the resistance to the ICI therapy, particularly focusing on myeloid cells, including unique subsets expressing IC molecules. A deeper understanding of the molecular and cellular determinants may facilitate its practical implementation of targeting myeloid villains, and improve the clinical outcomes in the ICI therapy of gastrointestinal cancer.
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Affiliation(s)
- Chie Kudo-Saito
- Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan
- *Correspondence: Chie Kudo-Saito,
| | - Narikazu Boku
- Department of Oncology and General Medicine, Institute of Medical Science Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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High CHAF1A Expression Levels Are Positively-Correlated with PD-L1 Expression and Indicate Poor Prognosis in Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1323321. [PMID: 35911136 PMCID: PMC9325625 DOI: 10.1155/2022/1323321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/17/2022] [Indexed: 12/01/2022]
Abstract
Objective The aim of this study was to analyze the association between the expression of chromatin assembly factor 1 subunit A (CHAF1A) in gastric cancer (GC) and clinicopathological features, disease prognosis, and expression of programmed cell death-ligand 1 (PD-L1). Material and Methods. A total of 140 GC tissue specimens were collected between January 2013 and December 2017. CHAF1A expression in GC and paracancerous tissues was determined. Then, the associations between CHAF1A expression level in the collected tissues and clinicopathological features as well as PD-L1 expression level were investigated. Cox regression analyses were carried out to determine whether CHAF1A is an independent prognostic factor for GC. Finally, the association between CHAF1A expression levels and survival of the GC patients was investigated. Results A significantly higher level of CHAF1A expression in GC tissues was found compared to that in paracancerous tissues (p=0.042). CHAF1A expression level in GC tissues was found to be strongly associated with family history (p=0.005), smoking history (p=0.016), T stage (p=0.001), tumor marker AFP (p=0.017), tumor marker CEA (p=0.027), and PD-L1 expression (p=0.029). CHAF1A expression was also found to be positively correlated to PD-L1 expression (p=0.012). Moreover, high CHAF1A expression levels were found to lead to poor prognosis (p=0.019). Univariate and multivariate analyses all showed that CHAF1A was an independent poorer prognostic factor for gastric cancer (p=0.021, HR = 1.175, 95% CI: 1.090–2.890 for univariate analyses; p=0.014, HR = 2.191, 95% CI:1.170–4.105 for multivariate analyses). A high level of CHAF1A expression was thus found to be an independent risk factor for GC prognosis. Conclusion High CHAF1A expression is associated with poor GC prognosis and positively correlated to PD-L1 expression. Thus, CHAF1A expression level may be used as a novel biomarker for GC diagnosis.
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Expression and Clinical Significance of CMTM6 and PD-L1 in Triple-Negative Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8118909. [PMID: 35845949 PMCID: PMC9283057 DOI: 10.1155/2022/8118909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 01/02/2023]
Abstract
The CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) plays an extremely important role of the programed death receptor ligand-1 (PD-L1) protein. Our study is aimed at investigating the expression of CMTM6 and PD-L1 proteins in triple-negative breast cancer and their correlation with the clinical pathological data of patients. We selected 89 cases of triple-negative breast cancer and 62 cases of normal breast tissue specimens. Immunohistochemical methods were used to detect the expression levels of CMTM6 and PD-L1 and to carefully study differences in their expression. The expression of CMTM6 and PD-L1 in TNBC was higher than that in normal breast tissue, and the expression of the two was positively correlated (p < 0.05). In TNBC, CMTM6 expression is positively correlated with tumor size, lymph node metastasis, Ki67 proliferation index, and TNM stage (p < 0.05). PD-L1 expression is positively correlated with tumor size, lymph node metastasis, Ki67 proliferation index, TNM stage, and vascular infiltration (p < 0.05). Kaplan-Meier analysis showed that the positive expression of CMTM6 and PD-L1 had no correlation with the survival rate of patients (p > 0.05). According to KM-plotter, we found that a higher CMTM6 expression was positively related with relapse-free survival rate of patients (p < 0.05). A higher PD-L1 expression was positively correlated with relapse-free, overall, and distant metastasis survival rate of patients (p < 0.05). In timer database, we found a positive correlation between the expression of CMTM6 and PD-L1 in triple-negative breast cancer. Both CMTM6 and PD-L1 are highly expressed in TNBC, and their expressions are positively related. In the future, the two gene might become targets for the treatment of TNBC, providing a basis of clinical treatment of TNBC.
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Ribeiro HSC, Menezes JN, da Costa WL, F. de Jesus VH, Diniz AL, Godoy AL, de Farias IC, Torres SM, Neotti T, Mello CAL, Begnami MDFS, Dias‐Neto E, Riechelmann RP, Fernandez Coimbra FJ. PD‐L1 expression in gastric and gastroesophageal junction cancer patients treated with perioperative chemotherapy. J Surg Oncol 2022; 126:150-160. [DOI: 10.1002/jso.26929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/27/2022] [Accepted: 05/08/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Héber S. C. Ribeiro
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Wilson L. da Costa
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
- Department of Medicine/Epidemiology and Population Sciences Baylor College of Medicine Houston Texas USA
| | | | - Alessandro L. Diniz
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - André L. Godoy
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Silvio M. Torres
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - Tatiane Neotti
- Department of Pathology A. C. Camargo Cancer Center São Paulo Brazil
| | - Celso A. L. Mello
- Department of Clinical Oncology A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Emmanuel Dias‐Neto
- Laboratory of Medical Genomics A. C. Camargo Cancer Center São Paulo Brazil
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Feasibility and Tolerance of Apatinib plus PD-1 Inhibitors for Previously Treated Advanced Gastric Cancer: A Real-World Exploratory Study. DISEASE MARKERS 2022; 2022:4322404. [PMID: 35531474 PMCID: PMC9076296 DOI: 10.1155/2022/4322404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/10/2022] [Accepted: 04/15/2022] [Indexed: 12/24/2022]
Abstract
Background Apatinib is established to be the standard of care as third-line therapy for patients with previously treated advanced gastric cancer (GC). Programmed cell death protein 1 (PD-1) blockades also exhibited promising efficacy and safety for patients with treatment-refractory advanced GC. Objective This study was to explore the feasibility and tolerance of apatinib plus PD-1 inhibitors for patients with previously treated advanced GC. Methods This study was performed as a real-world study; patients with advanced GC who were treated with previous systemic chemotherapy were screened retrospectively. Eligible patients were administered with apatinib combined with PD-1 blockade treatment. Efficacy of the patients was assessed with the change of target lesion using radiological evidence according to RECIST 1.1 criteria, and follow-up was carried out regularly. A safety profile was collected and documented during the combination treatment. Univariate analysis based on baseline characteristic subgroup was implemented in univariate analysis to identify the potential factor that might contribute to progression-free survival (PFS). Results Between August 2018 and October 2021, a total of 39 patients with advanced GC or gastroesophageal junction adenocarcinoma participated in this study consecutively and all the patients were available for efficacy and safety assessment. The best overall response during apatinib plus PD-1 blockade administration exhibited that PR was observed in 8 patients, SD was noted in 19 patients, and PD was found in 12 patients, which yielded an ORR of 20.5% (95% CI: 9.3%-36.5%), and DCR was 69.2% (95% CI: 52.4%-83.0%). Furthermore, the relatively enough follow-up had resulted in the mature PFS and overall survival (OS) data, suggesting that the median PFS of the 39 patients with advanced GC was 3.9 months (95% CI: 2.74-5.06). Additionally, the median OS of the 39 patients with advanced GC was 7.8 months (95% CI: 4.82-10.78). Furthermore, the most common adverse reactions of the 39 patients who received apatinib plus PD-1 blockades treatment were fatigue (61.5%), nausea and vomiting (56.4%), diarrhea (48.7%), hypertension (46.2%), hand-foot syndrome (38.5%), and rash (28.2%). Furthermore, performance status was independently associated with PFS of apatinib plus PD-1 inhibitor combination administration in baseline characteristic subgroup analysis. Conclusion Apatinib plus PD-1 inhibitors exhibited promising effectiveness and acceptable tolerance for previously treated advanced GC preliminarily. And this conclusion should be confirmed in clinical trials in the future.
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An Immunity-Associated lncRNA Signature for Predicting Prognosis in Gastric Adenocarcinoma. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:3035073. [PMID: 35509706 PMCID: PMC9061059 DOI: 10.1155/2022/3035073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/05/2022] [Accepted: 03/31/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric adenocarcinoma (GAD) is one of the most common tumors in the world and the prognosis is still very poor. Objective We sought to identify reliable prognostic biomarkers for the progression of GAD and the sensitivity to drug therapy. Method The RNA sequencing data of GAD was downloaded from the Cancer Genome Atlas (TCGA) database and used for analysis. Differentially expressed, immune-related lncRNA (DEIRlncRNA) was characterized by differential analysis and correlation analysis. Univariate Cox regression analysis was used to identify DEIRlncRNA associated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression analysis allowed us to determine a signature composed of eight IRlncRNAs. Based on this signature, we further performed gene set enrichment analysis (GSEA) and somatic mutation analysis to evaluate the ability of this signature to predict prognosis. Results In total, 72 immune-related lncRNAs (DEIRlncRNAs) with prognostic value were identified. These lncRNAs were used to construct a model containing eight immune-related lncRNAs (8-IRlncRNAs). Based on this risk model, we divided GAD patients into high-risk and low-risk groups. The analysis showed that the prognosis of the two groups was different and that the high-risk group had worse overall survival (OS). Immune cell infiltration analysis showed that the proportion of memory B cells increased in the high-risk group while the proportion of macrophages M1, T cells, CD4 memory-activated cells, and T cell follicular helpers decreased. GSEA results showed that 8-IRlncRNA was significantly enriched in tumorigenesis pathways such as myc. The results of somatic mutation analysis showed that the CDH1 gene was significantly mutated in the high-risk group. Conclusion A prognostic signature of 8-IRlncRNAs in GAD was established and this signature was able to predict the prognosis of GAD patients.
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Shi Y, Zheng H, Wang M, Ding S. Influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy needs more attention. Helicobacter 2022; 27:e12878. [PMID: 35112435 DOI: 10.1111/hel.12878] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVE The tumor microenvironment and tumor immunity are crucially involved in tumor therapy. Immune checkpoint inhibitors targeting PD-1/PD-L1 signal transduction have been widely used in tumor therapy and have shown ideal clinical efficacy. However, some kinds of cancers still do not respond to PD-1/PD-L1 blockade therapy effectively, including gastric cancer. The related factors should be explored. METHODS AND RESULTS This review summarizes the recent progression of understanding the influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy. Current pieces of evidence have indicated that H. pylori infection might affect the curative effect of tumor therapy associating with the induced immunomodulation. CONCLUSION It is necessary to understand the overall integration of PD-1/PD-L1 blockade therapy, the tumor microenvironment, and H. pylori infection. Much attention on the influence of H. pylori infection on the efficacy of tumor immunotherapy should be paid.
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Affiliation(s)
- Yanyan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | - Huiling Zheng
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Mopei Wang
- Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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Hassen G, Kasar A, Jain N, Berry S, Dave J, Zouetr M, Priyanka Ganapathiraju VLN, Kurapati T, Oshai S, Saad M, Pathan J, Kamat S, Tirupathi R, Patel UK, Rana RK. Programmed Death-Ligand 1 (PD-L1) Positivity and Factors Associated with Poor Prognosis in Patients with Gastric Cancer: An Umbrella Meta-Analysis. Cureus 2022; 14:e23845. [PMID: 35530821 PMCID: PMC9076041 DOI: 10.7759/cureus.23845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies throughout the world with late diagnosis and poor prognosis. The expression of programmed death-ligand 1 (PD-L1) in GC is attributed to immune evasion and tumor progression. PD-L1 positivity has both predictive and prognostic biomarker potential. Aiming to summarize a large amount of research and to provide a definitive conclusion to the conflicting results on the prognostic significance of PD-L1 expression in GC, we performed an umbrella review based on existing meta-analyses which were published recently (2016-2021) and indexed in the PubMed database. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used in August 2021 to screen articles, and data extraction with quality assessment was performed on the selected meta-analyses. Review Manager (RevMan) 5.3 software was used to analyze the HR and OR with a 95% confidence interval (CI) among PD-L1 positive GC patients. We also assessed the between-study heterogeneity (I 2). Forest and Funnel plots were obtained, and a P-value of <0.05 was considered statistically significant. A total of 567 articles were screened, and we selected three meta-analyses with a total of 40 studies conducted over a period of 14 years. In our umbrella review, a total of 8,419 GC patients with an average PD-L1 positivity of 39% were analyzed. We found that PD-L1 positivity in GC patients is associated with poor prognosis (pooled HR =1.44, 95% CI: 1.24-1.68, P<0.00001) having higher mortality reducing the chances of overall survival (OS). However, there are no significant differences in PD-L1 expression among different lymph node (LN) metastases (OR=1.31, 95% CI: 0.98-1.74, P=0.07) and tumor, node, and metastasis (TNM) stages (OR=1.13, 95% CI: 0.80-1.58, P=0.50). Early identification of PD-L1 expression may help tailor cost-effective and targeted immunotherapy among GC patients. More research is needed to further understand how PD-L1 affects LN metastasis and tumor invasion.
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Affiliation(s)
- Gashaw Hassen
- Progressive Care, Mercy Medical Center, Baltimore, USA.,Medicine and Surgery, Parma University, Parma, ITA.,Medicine, Addis Ababa University, Addis Ababa, ETH
| | - Amita Kasar
- Internal Medicine, Krishna Institute of Medical Sciences, Secunderabad, IND
| | - Nidhi Jain
- Medicine and Surgery, Himalayan Institute of Medical Sciences, Dehradun, IND.,Hematology and Oncology, Brooklyn Cancer Care, Brooklyn, USA.,Internal Medicine, Sir Ganga Ram Hospital, New Delhi, IND
| | - Shivankshi Berry
- Internal Medicine, Dayanand Medical College and Hospital, Ludhiana, IND.,Internal Medicine, Nassau University Medical Center, New York, USA
| | - Jhanvi Dave
- Internal Medicine, B.J. Medical College, Ahmedabad, IND
| | - Michlene Zouetr
- Family Medicine, American Institute of Antigua College of Medicine, St John's, ATG
| | | | | | - Stephanie Oshai
- Medicine and Surgery, College of Medicine, University of Lagos, Lagos, NGA
| | - Mohamed Saad
- Gastroenterology, Theodor Bilharz Research Institute, Giza, EGY
| | | | | | | | - Urvish K Patel
- Public Health and Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Rishabh K Rana
- Preventive and Social Medicine/Community Medicine, Shahid Nirmal Mahto Medical College, Dhanbad, Dhanbad, IND
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Recent insights into the use of immune checkpoint inhibitors in gastric cancer. Porto Biomed J 2022; 7:e162. [PMID: 35146175 PMCID: PMC8824404 DOI: 10.1097/j.pbj.0000000000000162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 11/26/2022] Open
Abstract
Gastric cancer (GC) is the fifth most incident and the fourth deadliest cancer worldwide. GC is a heterogeneous disease from the histological and molecular standpoints. This malignancy is mostly diagnosed at advanced stages of the disease, where the available therapeutic interventions are not effective. The emergence of immunotherapy has transformed the landscape of cancer treatment, including GC, and currently immune checkpoint inhibitors have been approved for the treatment of patients with recurrent/metastatic GC. This review summarizes the main clinical trials evaluating the use of immune checkpoint inhibitors in GC. It also highlights the potential of biomarkers for patient selection for GC immune checkpoint inhibition therapy, including programmed cell death ligand 1 expression and tumor mutational burden, and characteristics of the GC molecular classification, such as microsatellite instability status and Epstein-Barr virus infection, as predictors of response to blockade of the programmed cell death 1/programmed cell death ligand 1 axis.
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Qian Y, Su H, Ge Y, Lei K, Li Y, Fan H. Prognostic value of PD-L1 expression combined with hypoxia-associated immunosuppression in hepatocellular carcinoma. Biomark Med 2022; 16:435-448. [PMID: 35212229 DOI: 10.2217/bmm-2021-1051] [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: 11/21/2022] Open
Abstract
Background: Hypoxia and immunosuppression are two properties of cancer. This study intends to establish the potential relationship between these two hallmarks in hepatocellular carcinoma (HCC). Materials & methods: A bioinformatics analysis of data obtained from the Cancer Genome Atlas and a retrospective single-center analysis based on a tissue microarray were utilized in this study. Results: We identified a hypoxia-high subtype of patients with immunosuppressive HCC which represented a poor prognosis in the Cancer Genome Atlas cohort. Immunohistochemical analysis of the tissue microarray showed that tumor PD-L1 expression was positively linked to HIF-1α expression, pro-tumor immunocyte infiltration and poor survival in HCC patients. Conclusion: This study provides evidence supporting the correlation between hypoxic signals and immunosuppression in HCC; the combined use of them might improve survival prediction and act as a potential predictor for PD-1/PD-L1 therapy.
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Affiliation(s)
- Yanyan Qian
- Department of Medical Genetics & Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes & Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Hongmeng Su
- Department of Medical Genetics & Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes & Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Yanping Ge
- Department of Medical Genetics & Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes & Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Kai Lei
- Medical School, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Yiping Li
- Department of Pathology, Medical School, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Hong Fan
- Department of Medical Genetics & Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes & Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, China
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Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis. Diagnostics (Basel) 2021; 11:diagnostics11122370. [PMID: 34943606 PMCID: PMC8700640 DOI: 10.3390/diagnostics11122370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023] Open
Abstract
To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival.
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Xing F, Liu YC, Huang S, Lyu X, Su SM, Chan UI, Wu PC, Yan Y, Ai N, Li J, Zhao M, Rajendran BK, Liu J, Shao F, Sun H, Choi TK, Zhu W, Luo G, Liu S, Xu DL, Chan KL, Zhao Q, Miao K, Luo KQ, Ge W, Xu X, Wang G, Liu TM, Deng CX. Accelerating precision anti-cancer therapy by time-lapse and label-free 3D tumor slice culture platform. Theranostics 2021; 11:9415-9430. [PMID: 34646378 PMCID: PMC8490519 DOI: 10.7150/thno.59533] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/29/2021] [Indexed: 11/30/2022] Open
Abstract
The feasibility of personalized medicine for cancer treatment is largely hampered by costly, labor-intensive and time-consuming models for drug discovery. Herein, establishing new pre-clinical models to tackle these issues for personalized medicine is urgently demanded. Methods: We established a three-dimensional tumor slice culture (3D-TSC) platform incorporating label-free techniques for time-course experiments to predict anti-cancer drug efficacy and validated the 3D-TSC model by multiphoton fluorescence microscopy, RNA sequence analysis, histochemical and histological analysis. Results: Using time-lapse imaging of the apoptotic reporter sensor C3 (C3), we performed cell-based high-throughput drug screening and shortlisted high-efficacy drugs to screen murine and human 3D-TSCs, which validate effective candidates within 7 days of surgery. Histological and RNA sequence analyses demonstrated that 3D-TSCs accurately preserved immune components of the original tumor, which enables the successful achievement of immune checkpoint blockade assays with antibodies against PD-1 and/or PD-L1. Label-free multiphoton fluorescence imaging revealed that 3D-TSCs exhibit lipofuscin autofluorescence features in the time-course monitoring of drug response and efficacy. Conclusion: This technology accelerates precision anti-cancer therapy by providing a cheap, fast, and easy platform for anti-cancer drug discovery.
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Song DW, Ro WB, Park HM. Evaluation of circulating PD-1 and PD-L1 as diagnostic biomarkers in dogs with tumors. J Vet Sci 2021; 22:e75. [PMID: 34553519 PMCID: PMC8460464 DOI: 10.4142/jvs.2021.22.e75] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/15/2021] [Accepted: 08/24/2021] [Indexed: 12/21/2022] Open
Abstract
Background Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have important roles in tumor evasion of the immune system. Objectives This study aimed to assess the diagnostic utility of circulating PD-1 and PD-L1 levels in healthy dogs and dogs with tumors. Methods Circulating PD-1 and PD-L1 levels in the serum of 71 dogs with tumors were compared with those of 52 healthy dogs by performing enzyme-linked immunosorbent assay (ELISA). Results The ELISA results revealed higher circulating PD-1 and PD-L1 levels in dogs with tumors (2.9 [2.2–3.7] ng/mL; median [IQR] and 2.4 [1.4–4.4] ng/mL, respectively) than in healthy dogs (2.4 [1.9–3.0] ng/mL; p = 0.012 and 1.4 [0.9–2.1] ng/mL; p < 0.001, respectively). Especially, there was a significant difference in circulating PD-1 levels between healthy dogs and dogs with malignant epithelial tumors (2.4 [1.9–3.0] ng/mL and 3.1 [2.6–4.4] ng/mL, respectively; p < 0.01). In addition, there was a significant difference in circulating PD-L1 levels between healthy dogs and dogs with lymphomas (1.4 [0.9–2.1] ng/mL and 2.7 [1.6–5.8] ng/mL, respectively; p < 0.001). Conclusion This study indicates that circulating PD-1 and PD-L1 have potential as tumor diagnostic biomarkers in dogs with tumors.
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Affiliation(s)
- Doo-Won Song
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
| | - Woong-Bin Ro
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
| | - Hee-Myung Park
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea.
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Huynh J, Patel K, Gong J, Cho M, Malla M, Parikh A, Klempner S. Immunotherapy in Gastroesophageal Cancers: Current Evidence and Ongoing Trials. Curr Treat Options Oncol 2021; 22:100. [PMID: 34524553 DOI: 10.1007/s11864-021-00893-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2021] [Indexed: 12/13/2022]
Abstract
OPINION STATEMENT Data supporting the use of immunotherapy in the treatment of gastroesophageal cancer continues to evolve. The promising results from adjuvant immunotherapy and trials combining immunotherapy plus chemotherapy in the 1L setting have led to broad US FDA approvals. Among the PD-L1 negative subgroups, the magnitude of benefit is diminished; effective therapy for this population remains an unmet need. A detailed biologic understanding of the PD-L1 negative (and low) population represents a barrier to developing effective combination therapies, although combination angiogenesis inhibitors and immunotherapy look encouraging. Early phase clinical trials, particularly with pembrolizumab plus lenvatinib (EPOC 1706), demonstrated a clear signal independent of PD-L1, and a confirmatory phase III trial of pembrolizumab plus lenvatinib is planned. Conceptually, it is important to think of immune checkpoint inhibitor therapy as targeted therapy, most active in clearly defined biomarker-selected populations. Pre-planned analyses have reliably shown a clear trend toward a greater magnitude of benefit in patients with higher PD-L1 expression, particularly CPS ≥ 5 and ≥ 10. Whether there is a linear relationship at higher cutoffs is not well known, though it likely represents smaller and smaller populations. Although beyond the scope of this clinically oriented review, recognition of the spatial and temporal heterogeneity in PD-L1 expression is important and repeat testing from progression samples across lines of therapy should be considered. Questions about additional predictive biomarkers, particularly plasma-derived, remain. Responses by tumor histology and location also differ, and special attention to these factors as well as MSI-H, HER2, and EBV subgroups in future trials is warranted. Questions regarding the incorporation of immunotherapy after progression on 1L immunotherapy plus chemotherapy combinations will arise as these combinations are used more frequently, and this represents a key area of future investigation. Overall, the role of immunotherapy continues to expand in GEA, and we welcome any additional tools for this difficult-to-treat group of cancers.
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Affiliation(s)
- Jasmine Huynh
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Kanishka Patel
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Jun Gong
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CA, USA
| | - May Cho
- University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA
| | - Midhun Malla
- West Virginia Cancer Institute, Morgantown, WV, USA
| | - Aparna Parikh
- Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
| | - Samuel Klempner
- Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
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Abstract
PURPOSE OF REVIEW Ovarian cancer (OC) is a heterogeneous disease and a mounting body of evidence shows that a 'one-size-fits-all' approach is obsolete. Differences in epidemiology, tumor biology, genetic profiles and treatment responses of these different types necessitate a tumor and patient-specific approach. Ninety percentage consists of epithelial OC with 70% being high-grade serous OC. The other rarer subtypes are low-grade serous (5%), clear cell (12%), endometrioid (11%) and mucinous carcinoma (3%). The remaining 10% are nonepithelial rare OCs: germ cell (3%) and sex-cord stromal tumors (7%). RECENT FINDINGS Over the past few decades, the 5-year survival rates have only improved modestly, therefore novel therapies are urgently needed. Recently, immunotherapy has been introduced into clinical practice in a number of solid tumors. Although preclinical data confirm the presence of an immunogenic microenvironment in a number of ovarian tumor types, no single-agent immune checkpoint inhibitor has been approved hitherto. Identifying suitable treatment combinations, adequate patient selection and thus correct implementation of immunotherapy remain major challenges. SUMMARY In this review, we focus on the rationale of incorporating immune therapy in rare OC, we summarize the recent developments with preclinical data and results of clinical trials, with particular focus on rare ovarian histological subtypes.
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Affiliation(s)
- Tina Laga
- Division of Gynecological Oncology, Department of Gynecology and Obstetrics and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
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PD-L1 Expression Is a Favorable Prognostic Marker in Gastric Carcinoma. Appl Immunohistochem Mol Morphol 2021; 28:748-754. [PMID: 32205740 DOI: 10.1097/pai.0000000000000834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. Although multidisciplinary therapeutic strategies have improved treatment outcomes, the overall prognosis for patients with GC remains poor. Recently, immunotherapeutic agents targeting immunosuppressive proteins such as anti-programmed death-1 receptor and anti-programmed death ligand-1 (PD-L1) have emerged as effective treatment options for various cancers, including GC. In addition to their therapeutic role, the expression of PD-L1 has been used as a predictive biomarker for programmed death-1/PD-L1 treatment response and has been shown to have a prognostic role in certain cancers. This study aims to evaluate the expression of PD-L1 in GC samples from Jordanian patients and assess its prognostic role as well as its correlation with clinicopathologic variables. Gastrectomy samples from 96 patients diagnosed with gastric adenocarcinoma were included in the study. Immunohistochemistry assay was employed for PD-L1 testing, and the scoring was based on a combined positive score (CPS). It was found that 66.7% of the study samples were positive for PD-L1 (CPS≥1). The expression of PD-L1 was not significantly associated with any of the assessed clinicopathologic variables; however, it was found to be an independent favorable prognostic factor for overall survival (hazard ratio: 0.481; 95% confidence interval: 0.231-1.001; P=0.050).
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Wu B, Gao J, Ma M, Wu Y, Ye X. Prognostic factor analysis for patient outcome of PD-L1 expression in thoracic oesophageal squamous cell carcinoma. Interact Cardiovasc Thorac Surg 2021; 33:564-571. [PMID: 34324661 DOI: 10.1093/icvts/ivab149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/19/2021] [Accepted: 04/20/2021] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The purpose of this study was to determine the expression of PD-L1 in oesophageal squamous cell carcinoma (OSCC) and the prognostic factors. METHODS PD-L1 expression was investigated by immunohistochemical staining of resected specimens from 50 OSCC patients who were randomly selected from 104 patients with complete follow-up data. The relationships among PD-L1 expression, clinicopathological factors and prognosis were assessed by statistical analysis. RESULTS The expression of PD-L1 was positive in 27 (54%, positive cells' proportion > 25%) and negative in 23 (46%, positive cells proportion ≤25%) of 50 cases, and PD-L1 expression was negative in all pericarcinomatous tissues (P > 0.05). The 5-year survival rate of patients with PD-L1-positive expression was 22.2% (6 of 27), which was less than that of patients with PD-L1-negative expression (47.8%; 11 of 23) (P < 0.05). The results showed significant differences in the depth of tumour invasion, lymph node status, postoperative pathological stage and PD-L1 expression (P < 0.05). Multivariable analysis showed that PD-L1 expression was an independent prognostic factor for survival. CONCLUSIONS The depth of tumour invasion, lymph node status, postoperative pathological stage and PD-L1 expression are important factors affecting the prognosis of patients with thoracic OSCC; in particular, high PD-L1 expression was a significant independent poor prognostic factor in thoracic OSCC patients.
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Affiliation(s)
- Bo Wu
- Department of Surgical Oncology II, General Hospital of Ningxia Medical University Cancer Hospital, Yinchuan, Ningxia, China
| | - Jianhua Gao
- Department of Surgical Oncology II, General Hospital of Ningxia Medical University Cancer Hospital, Yinchuan, Ningxia, China
| | - Muyuan Ma
- Department of Surgical Oncology II, General Hospital of Ningxia Medical University Cancer Hospital, Yinchuan, Ningxia, China
| | - Yuanyuan Wu
- Department of Surgical Oncology II, General Hospital of Ningxia Medical University Cancer Hospital, Yinchuan, Ningxia, China
| | - Xiaofeng Ye
- Department of Surgical Oncology II, General Hospital of Ningxia Medical University Cancer Hospital, Yinchuan, Ningxia, China
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Basile D, Simionato F, Calvetti L, Cappetta A, Pesavento A, Mongillo M, Roviello G, Rosati G, Rossi G, Aprile G. Comparing immunotherapies to other frequently used treatments of gastric cancer. Expert Rev Clin Pharmacol 2021; 14:1221-1232. [PMID: 34114518 DOI: 10.1080/17512433.2021.1938546] [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: 12/07/2022]
Abstract
Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.
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Affiliation(s)
- Debora Basile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Lorenzo Calvetti
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Annalisa Pesavento
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.,Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Marta Mongillo
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.,Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | | | - Gerardo Rosati
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Gemma Rossi
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
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Xu J, Wen J, Li S, Shen X, You T, Huang Y, Xu C, Zhao Y. Immune-Related Nine-MicroRNA Signature for Predicting the Prognosis of Gastric Cancer. Front Genet 2021; 12:690598. [PMID: 34290743 PMCID: PMC8287335 DOI: 10.3389/fgene.2021.690598] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 12/21/2022] Open
Abstract
Recent findings have demonstrated the superiority and utility of microRNAs (miRNAs) as new biomarkers for cancer diagnosis, therapy, and prognosis. In this study, to explore the prognostic value of immune-related miRNAs in gastric cancer (GC), we analyzed the miRNA-expression profiles of 389 patients with GC, using data deposited in The Cancer Genome Atlas database. Using a forward- and backward-variable selection and multivariate Cox regression analyses model, we identified a nine-miRNA signature (the “ImmiRSig,” consisting of miR-125b-5p, miR-99a-3p, miR-145-3p, miR-328-3p, miR-133a-5p, miR-1292-5p, miR-675-3p, miR-92b-5p, and miR-942-3p) in the training cohort that enabled the division of patients into high- and low-risk groups with significantly different survival rates. The ImmiRSig was successfully validated with an independent test cohort of 193 GC patients. Univariate and multivariate Cox regression analyses indicated that the ImmiRSig would serve as an independent prognostic factor after adjusting for other clinical covariates. Pending further prospective validation, the identified ImmiRSig appears to have significant clinical importance in terms of improving outcome predictions and guiding personalized treatment for patients with GC. Finally, significant associations between the ImmiRSig and the half-maximal inhibitory concentrations of chemotherapeutic agents were observed, suggesting that ImmiRSig may predict the clinical efficacy of chemotherapy.
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Affiliation(s)
- Jingxuan Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jian Wen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shuangquan Li
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Tao You
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yingpeng Huang
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Chongyong Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yaping Zhao
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Sue-A-Quan R, Patel PG, Shakfa N, Nyi MPN, Afriyie-Asante A, Kang EY, Köbel M, Koti M. Prognostic significance of T cells, PD-L1 immune checkpoint and tumour associated macrophages in clear cell carcinoma of the ovary. Gynecol Oncol 2021; 162:421-430. [PMID: 34088514 DOI: 10.1016/j.ygyno.2021.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/09/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To define the pre-treatment tumour immune landscape of clear cell carcinoma of the ovary (CCOC). METHODS We investigated the infiltration profiles of selected immune cell populations and immune checkpoint proteins that have been previously shown to have prognostic relevance in high grade serous carcinoma of the ovary to determine their association with clinical outcomes in CCOC patients. Using multiplex immunohistochemistry, we evaluated the density of CD3+, FoxP3+, CD8+ T cells, CD20+ B cells and expression of PD-1, PD-L1 and IDO1 immune checkpoints in a cohort of 162 CCOC tumour specimens on a tissue microarray. RESULTS Increased infiltration of CD3+ CD8- (helper T) cells, CD8+ (cytotoxic T) cells, and CD68+ macrophages significantly associated with shorter disease-free survival, recurrence-free survival and overall survival. Importantly, higher expression of PD-L1 and IDO-1 immune checkpoints was associated with better clinical outcomes. CONCLUSION Findings from our study are foundational towards the development of immune classifiers and biomarkers of response to immune checkpoint blockade therapy in CCOC.
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Affiliation(s)
- Rachel Sue-A-Quan
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Palak G Patel
- Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Noor Shakfa
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - May-Phyo Nyi Nyi
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Afrakoma Afriyie-Asante
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Eun Young Kang
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Madhuri Koti
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; Department of Obstetrics and Gynecology, Kingston Health Sciences Center, Queen's University, Kingston, Canada.
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Feng X, Xue F, He G, Huang S, Ni Q. Banxia Xiexin Decoction Inhibits the Expression of PD-L1 Through Multi-Target and Multi-Pathway Regulation of Major Oncogenes in Gastric Cancer. Onco Targets Ther 2021; 14:3297-3307. [PMID: 34040394 PMCID: PMC8141399 DOI: 10.2147/ott.s288442] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose Banxia xiexin decoction (BXXX) is a classical Chinese herbal compound for the treatment of gastrointestinal diseases. Its ingredients are also considered helpful for cancer rehabilitation. Here, we will explore the regulatory mechanism of BXXX acting on PD-L1 in gastric cancer (GC). Methods GC samples and the general baseline data of the patients were collated. Immunohistochemical (IHC) detected the expression of programmed cell death-ligand 1(PD-L1), hypoxia-inducible factor-1 (HIF-1), epidermal growth factor receptor (EGFR), interferon-γ receptor (IFNGR) and Toll-like receptor 4 (TLR4). ELISA detected the expressions of EGF, IFNG and IL-6 in serum samples. Network tools were used to analyze the potential molecules of BXXX. In the cell experiment, CCK-8 detected the cell proliferation. Tunel detected the apoptosis. Western blot detected the expression of related proteins. In animal experiments, the tumor volume of GC-bearing mice was observed. Expression of EGF, IFNG and IL-6 in the serum of tumor-bearing GC mice were detected by ELISA. Western blot detected the expression of related proteins. Results The expressions of PD-L1, HIF-1, EGFR, IFNGR and TLR4 in the tissues of GC patients were significantly increased, and the expressions of EGF, IFNG and IL-6 in serum were increased. The molecular results of the network tools showed that BXXX and its main components have a targeting effect on the key molecules of each pathway in the PD-L1 regulatory network. Cell experiments showed that BXXX can inhibit the expression of PD-L1, HIF-1, EGFR and TLR4, but has no significant effect on the expression of IFNGR, thus inhibiting the proliferation and promoting the apoptosis of GC cells. The results were consistent with the animal experiments on tumor-bearing gastric cancer mice. Conclusion BXXX inhibited the expression of PD-L1 through multi-target and multi-pathway regulation of major oncogenes in GC, thus effect cell proliferation and apoptosis.
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Affiliation(s)
- Xuan Feng
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, People's Republic of China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225001, Jiangsu, People's Republic of China
| | - Feng Xue
- Department of Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, 225000, Jiangsu, People's Republic of China
| | - Guihua He
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, People's Republic of China
| | - Suiping Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, People's Republic of China
| | - Qing Ni
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, People's Republic of China.,Department of Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, 225000, Jiangsu, People's Republic of China
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48
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Lee W, Kim MJ, Choi Y, Kim H. PD-L1 expression and patient outcomes in gastrointestinal neuroendocrine neoplasm: a meta-analysis. Transl Cancer Res 2021; 10:2210-2218. [PMID: 35116539 PMCID: PMC8798646 DOI: 10.21037/tcr-20-3482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/24/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Programmed cell death ligand 1 (PD-L1) is a known prognostic and therapeutic marker in malignant tumors. This meta-analysis aimed to investigate the association of PD-L1 expression with the clinicopathological parameters and survival outcomes of gastrointestinal neuroendocrine neoplasms (NENs). METHODS PubMed, EMBASE, Web of Science, OVID Medline, the Cochrane Library, and Google Scholar were searched for relevant studies June 30, 2020. Studies reporting PD-L1 immunohistochemistry of gastrointestinal NEN with associated survival data or clinicopathological parameters were included. RESULTS In total, 10 studies were included. Odd ratios (ORs) were combined to evaluate association between PD-L1 expression and clinicopathological parameters. Hazard ratios (HR) and standard errors were combined to evaluate the association between PD-L1 expression and overall survival. PD-L1 expression was significantly associated with higher tumor grade [OR: 3.42; 95% confidence interval (CI): 2.00-5.85, P<0.05] and lymph node metastasis (OR: 1.94; 95% CI: 1.13-3.34, P=0.02). However, PD-L1 expression was not associated with age, sex, and tumor stage. The pooled hazard ratio (HR: 2.45, 95% CI: 1.20-4.98, P<0.05) showed a significant association between PD-L1 expression and shorter overall survival. DISCUSSION The results of this meta-analysis show that PD-L1 expression in tumor cells of gastrointestinal NEN can be used as a biomarker of worse survival and important clinicopathological parameters. Further, it can also be used as a therapeutic biomarker for developing novel treatment modalities that can improve prognosis. Although the results of this meta-analysis are more robust than those of the individual studies analyzed, this study also has several limitations. Further studies with a larger study population and consistent method for evaluating PD-L1 expression are needed to validate our results.
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Affiliation(s)
- Woojoo Lee
- Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Min-Ju Kim
- Department of Pathology, Soonchunhyang University College of Medicine, Bucheon Hospital, Gyeonggi-do, Republic of Korea
| | - Younghee Choi
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Gyeonggi-do, Republic of Korea
| | - Hyunchul Kim
- Department of Pathology, CHA Ilsan Medical Center, Gyeonggi-do, Republic of Korea
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Park R, Da Silva LL, Saeed A. Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond. Cancers (Basel) 2021; 13:1715. [PMID: 33916348 PMCID: PMC8038572 DOI: 10.3390/cancers13071715] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022] Open
Abstract
Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.
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Affiliation(s)
- Robin Park
- Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA; (R.P.); (L.L.D.S.)
| | - Laercio Lopes Da Silva
- Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA 01702, USA; (R.P.); (L.L.D.S.)
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS 66205, USA
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50
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Lau DK, Athauda A, Chau I. Neoadjuvant and adjuvant multimodality therapies in resectable esophagogastric adenocarcinoma. Expert Opin Pharmacother 2021; 22:1429-1441. [PMID: 33688789 DOI: 10.1080/14656566.2021.1900823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Gastric and esophageal adenocarcinoma is a leading cause of cancer-related death globally. Surgery is the cornerstone modality for cure where feasible. Clinical studies over the past two decades have provided evidence for the use of perioperative chemotherapy and chemoradiotherapy to improve patient outcomes. However, there remains no global consensus in the optimal use of these therapies.Areas covered: In this review, the authors summarize the latest evidence for perioperative multimodality therapy in resectable esophagogastric adenocarcinoma including the use of combination chemotherapy and targeted therapy containing regimens. In addition, the authors discuss some of the clinical and molecular biomarkers, such as PET imaging and microsatellite instability which can inform future practice and further clinical investigation.Expert opinion: A multimodal approach has been proven to improve survival outcomes over surgery alone. Whilst there is no global standard of care for multi-modality therapies in resectable OG cancer, clinical trials are refining the use of chemotherapy and radiotherapy in the neoadjuvant and adjuvant settings. Further investigation is on-going to further optimize therapy and the integration of molecular targeted agents.
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Affiliation(s)
- David K Lau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Avani Athauda
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Ian Chau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
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