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Zhang Z, Zhang W, Liu X, Yan Y, Fu W. T lymphocyte‑related immune response and immunotherapy in gastric cancer (Review). Oncol Lett 2024; 28:537. [PMID: 39319215 PMCID: PMC11421013 DOI: 10.3892/ol.2024.14670] [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: 05/29/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
Gastric cancer (GC) remains a global healthcare challenge because of its high incidence and poor prognosis. The efficacy of current chemotherapy regimens for advanced GC is limited. T cells, which have been implicated in the progression of GC, have a significant impact in the tumor microenvironment. With a more detailed understanding of the mechanisms underlying the cancer immunoediting process, immunotherapy may become a promising treatment option for patients with GC. Several clinical trials are currently investigating different mechanisms targeting the tumor immune response. The present review summarized T cell-involved immune responses and various immunotherapy strategies for GC.
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Affiliation(s)
- Zhaoxiong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Wenxin Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yongjia Yan
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Weihua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Dong H, Yao L, Fan J, Gao P, Yang X, Yuan Z, Zhang T, Lu M, Chen X, Suo C. Characteristics of auto-quantified tumor-infiltrating lymphocytes and the prognostic value in adenocarcinoma of the esophagogastric junction, gastric adenocarcinoma, and esophageal squamous cell carcinoma. Aging (Albany NY) 2024; 16:11027-11061. [PMID: 38975889 PMCID: PMC11272125 DOI: 10.18632/aging.205999] [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: 10/04/2023] [Accepted: 06/10/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND Adenocarcinoma of the esophagogastric junction (AEGJ) with a specific pathological profile and poor prognosis has limited therapeutic options. Previous studies have found that TILs exhibit distinct characteristics in different tumors and are correlated with tumor prognosis. We established cellular training sets to obtain auto-quantified TILs in pathological images. And we compared the characteristics of TILs in AEGJ with those in esophageal squamous cell carcinoma (ESCC) and gastric adenocarcinoma (GAC) to gain insight into the unique immune environments of these three tumors and investigate the prognostic value of TILs in these three tumors. METHODS Utilizing a case-control study design, we analyzed 214 AEGJ, 256 GAC, and 752 ESCC cases. The TCGA dataset was used to validate prognostic value of auto-quantified TILs. The specific cellular training sets were established by experienced pathologists to determine TILs counts. Kruskal-Wallis test and multi-variable linear regression were conducted to explore TILs characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. RESULTS The three cellular training sets of these cancers achieved a classification accuracy of 87.55 at least. The median auto-quantified TILs of AEGJ, GAC, and ESCC cases were 4.82%, 1.92%, and 0.12%, respectively. The TILs demonstrated varied characteristics under distinctive clinicopathological traits. The higher TILs proportion was associated with better prognosis in esophagogastric cancers (all P < 0.05) and was an independent prognostic biomarker on AEGJ in both datasets (Taixing: HR = 0.965, 95% CI = 0.938-0.994; TCGA: HR = 0.811, 95% CI = 0.712-0.925). CONCLUSIONS We found variations in TILs across ESCC, GAC, and AEGJ, as assessed by image processing algorithms. Additionally, TILs in these three cancers are an independent prognostic factor. This enhances our understanding of the unique immune characteristics of the three tumors, improving patient outcomes.
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Affiliation(s)
- Hao Dong
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
| | - Longqing Yao
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
| | - Jiahui Fan
- Department of Clinical Laboratory, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Peipei Gao
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Xiaorong Yang
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Ziyu Yuan
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Tiejun Zhang
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Ming Lu
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China
| | - Chen Suo
- Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
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Yavuz A, Simsek K, Alpsoy A, Altunay B, Gedik EO, Unal B, Bassorgun CI, Tatli AM, Elpek GO. Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma. World J Gastrointest Pathophysiol 2024; 15:91237. [PMID: 38682027 PMCID: PMC11045359 DOI: 10.4291/wjgp.v15.i1.91237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/08/2024] [Accepted: 03/22/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that pathological evaluation of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may be crucial in determining tumor behavior in the gastrointestinal tract. Regarding gastric adenocarcinoma (GAC), although some results suggest that TB and TILs may be effective in determining the course of the disease, the data do not agree. Moreover, very few studies have investigated the relationship between DR and survival. At present, the associations between tumor TB, DR and TILs in GAC patients have not been determined. AIM To establish the relationships between TB, DR, and TILs in patients with GAC and to assess their influence on prognosis. METHODS Our study group comprised 130 patients diagnosed with GAC. The definition of TB was established based on the International TB Consensus Conference. The DR was categorized into three groups according to the level of tumor stroma maturation. The assessment of TILs was conducted using a semiquantitative approach, employing a cutoff value of 5%. The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27. RESULTS A significant correlation between peritumoral budding (PTB) and intratumoral budding (ITB) was noted (r = 0.943). Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs (P < 0.01). PTB and ITB were associated with histological subtype, lymph node metastasis (LNM), and stage (P < 0.01). ITB, PTB, LNM, DR, and stage were significant risk factors associated with poor prognosis. The multivariate Cox regression analysis identified ITB, PTB, and LNM as independent prognostic variables (P < 0.05). In intestinal-type adenocarcinomas, a positive correlation between PTB and ITB was noted (r = 0.972). While univariate analysis revealed that LNM, stage, PTB, ITB, and DR were strong parameters for predicting survival (P < 0.05), only PTB and ITB were found to be independent prognostic factors (P < 0.001). CONCLUSION TB may be a potential prognostic marker in GAC. However, further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.
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Affiliation(s)
- Aysen Yavuz
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Kubra Simsek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Anil Alpsoy
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Busra Altunay
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Elif Ocak Gedik
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Betul Unal
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | | | - Ali Murat Tatli
- Department of Medical Oncology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
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Čeprnja T, Tomić S, Perić Balja M, Marušić Z, Blažićević V, Spagnoli GC, Juretić A, Čapkun V, Vuger AT, Pogorelić Z, Mrklić I. Prognostic Value of "Basal-like" Morphology, Tumor-Infiltrating Lymphocytes and Multi-MAGE-A Expression in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:4513. [PMID: 38674098 PMCID: PMC11050590 DOI: 10.3390/ijms25084513] [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: 04/01/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
"Basal-like" (BL) morphology and the expression of cancer testis antigens (CTA) in breast cancer still have unclear prognostic significance. The aim of our research was to explore correlations of the morphological characteristics and tumor microenvironment in triple-negative breast carcinomas (TNBCs) with multi-MAGE-A CTA expression and to determine their prognostic significance. Clinical records of breast cancer patients who underwent surgery between January 2017 and December 2018 in four major Croatian clinical centers were analyzed. A total of 97 non-metastatic TNBCs with available tissue samples and treatment information were identified. Cancer tissue sections were additionally stained with programmed death-ligand 1 (PD-L1) Ventana (SP142) and multi-MAGE-A (mAb 57B). BL morphology was detected in 47 (49%) TNBCs and was associated with a higher Ki-67 proliferation index and histologic grade. Expression of multi-MAGE-A was observed in 77 (79%) TNBCs and was significantly associated with BL morphology. Lymphocyte-predominant breast cancer (LPBC) status was detected in 11 cases (11.3%) and significantly correlated with the Ki-67 proliferation index, increased number of intratumoral lymphocytes (itTIL), and PD-L1 expression. No impact of BL morphology, multi-MAGE-A expression, histologic type, or LPBC status on disease-free survival was observed. Our data suggest that tumor morphology could help identify patients with potential benefits from CTA-targeting immunotherapy.
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Affiliation(s)
- Toni Čeprnja
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
| | - Snježana Tomić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
- Department of Pathology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Melita Perić Balja
- Department of Pathology, University Hospital Center “Sestre Milosrdnice”, 10000 Zagreb, Croatia
| | - Zlatko Marušić
- Department of Pathology, Zagreb University Hospital Center, 10000 Zagreb, Croatia
| | | | | | - Antonio Juretić
- Department of Oncology, University Hospital Dubrava, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Vesna Čapkun
- Department of Nuclear Medicine, University Hospital of Split, 21000 Split, Croatia
| | - Ana Tečić Vuger
- Department of Oncology, University Hospital “Sestre Milosrdnice”, 10000 Zagreb, Croatia;
| | - Zenon Pogorelić
- Department of Pediatric Surgery, University Hospital of Split, 21000 Split, Croatia
- Department of Surgery, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ivana Mrklić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia; (T.Č.); (S.T.); (I.M.)
- Department of Pathology, School of Medicine, University of Split, 21000 Split, Croatia
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Pereira MA, Ramos MFKP, Cardili L, de Moraes RDR, Dias AR, Szor DJ, Zilberstein B, Alves VAF, de Mello ES, Ribeiro U. Prognostic implications of tumor-infiltrating lymphocytes within the tumor microenvironment in gastric cancer. J Gastrointest Surg 2024; 28:151-157. [PMID: 38445936 DOI: 10.1016/j.gassur.2023.12.002] [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: 07/18/2023] [Revised: 10/05/2023] [Accepted: 11/30/2023] [Indexed: 03/07/2024]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) play a regulatory role in the tumor-associated immune response and are important in the prognosis and treatment response of several cancers. However, because of its heterogeneity, the prognostic value of TILs in gastric cancer (GC) is still controversial. Thus, this study aimed to investigate the association between the density of TILs and patients' outcomes in GC. METHODS Patients with gastric adenocarcinoma who underwent curative intent gastrectomy were retrospectively investigated. The groups for analysis were determined on the basis of TIL intensity and percentage of CD3+ T-cell infiltration by immunohistochemical. Furthermore, Epstein-Barr virus (EBV), microsatellite instability (MSI), T-cell ratio of CD4 to CD8, and programmed death protein ligand 1 (PD-L1) status were evaluated. RESULTS A total of 345 patients were enrolled: 124 patients with GCs (35.9%) were classified as the low-CD3+ TIL group, and 221 patients with GCs (64.1%) were classified as the high-CD3+ TIL group. Poorly differentiated histology (P = .014), EBV-positive status (P < .001), PD-L1-positive status (P = .001), and CD4 < CD8 (P < .001) were associated with high-CD3+ GC. There was no difference regarding MSI status, the degree of tumor invasion (pT), the presence of lymph node metastasis, and pTNM stage between low- and high-CD3+ groups. In survival analysis, the high-CD3+ group had better disease-free survival and overall survival rates than had the low-CD3+ group (P = .055 and P = .041, respectively). In the multivariate analysis, total gastrectomy, lymph node metastasis, advanced pT stage, and low CD3+ levels were independent factors related to worse survival. CONCLUSION High CD3+ TILs levels were significantly associated with improved survival and could serve as prognostic biomarkers in GC. In addition, CD3+ T-cell infiltration was related to both EBV-positive and PD-L1-positive GC and may assist in the investigation of targets in immunotherapy.
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Affiliation(s)
- Marina Alessandra Pereira
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil.
| | - Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Leonardo Cardili
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Rafael Dyer Rodrigues de Moraes
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - André Roncon Dias
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Daniel Jose Szor
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Bruno Zilberstein
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Evandro Sobroza de Mello
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas of the University of São Paulo, Universidade de São Paulo, São Paulo, Brazil
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Xu W, Chen S, Jiang Q, He J, Zhang F, Wang Z, Ruan C, Shi B. LUM as a novel prognostic marker and its correlation with immune infiltration in gastric cancer: a study based on immunohistochemical analysis and bioinformatics. BMC Gastroenterol 2023; 23:455. [PMID: 38129820 PMCID: PMC10740220 DOI: 10.1186/s12876-023-03075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is considered the sixth highly prevailing malignant neoplasm and is ranked third in terms of cancer mortality rates. To enable an early and efficient diagnosis of GC, it is important to detect the fundamental processes involved in the oncogenesis and progression of gastric malignancy. The understanding of molecular signaling pathways can facilitate the development of more effective therapeutic strategies for GC patients. METHODS The screening of genes that exhibited differential expression in early and advanced GC was performed utilizing the Gene Expression Omnibus databases (GSE3438). Based on this, the protein and protein interaction network was constructed to screen for hub genes. The resulting list of hub genes was evaluated with bioinformatic analysis and selected genes were validated the protein expression by immunohistochemistry (IHC). Finally, a competing endogenous RNA network of GC was constructed. RESULTS The three genes (ITGB1, LUM, and COL5A2) overexpressed in both early and advanced GC were identified for the first time. Their upregulation has been linked with worse overall survival (OS) time in patients with GC. Only LUM was identified as an independent risk factor for OS among GC patients by means of additional analysis. IHC results demonstrated that the expression of LUM protein was increased in GC tissue, and was positively associated with the pathological T stage. LUM expression can effectively differentiate tumorous tissue from normal tissue (area under the curve = 0.743). The area under 1-, 3-, and 5-year survival relative operating characteristics were greater than 0.6. Biological function enrichment analyses suggested that the genes related to LUM expression were involved in extracellular matrix development-related pathways and enriched in several cancer-related pathways. LUM affects the infiltration degree of cells linked to the immune system in the tumor microenvironment. In GC progression, the AC117386.2/hsa-miR-378c/LUM regulatory axis was also identified. CONCLUSION Collectively, a thorough bioinformatics analysis was carried out and an AC117386.2/hsa-miR-378c/LUM regulatory axis in the stomach adenocarcinoma dataset was detected. These findings should serve as a guide for future experimental investigations and warrant confirmation from larger studies.
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Affiliation(s)
- Wu Xu
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Shasha Chen
- Department of Pathology, Longyan Second Hospital, No.8 Shuangyang West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Qiuju Jiang
- Department of Pathology, Longyan Second Hospital, No.8 Shuangyang West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Jinlan He
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Feifei Zhang
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Zhuying Wang
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Caishun Ruan
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China
| | - Bin Shi
- Department of Medical Oncology, Longyan People's Hospital, No.31 Denggao West Road, Longyan, Fujian, 364000, People's Republic of China.
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Liu S, Liu X, Lin X, Chen H. Zinc Finger Proteins in the War on Gastric Cancer: Molecular Mechanism and Clinical Potential. Cells 2023; 12:cells12091314. [PMID: 37174714 PMCID: PMC10177130 DOI: 10.3390/cells12091314] [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: 04/11/2023] [Revised: 04/30/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
According to the 2020 global cancer data released by the World Cancer Research Fund (WCRF) International, gastric cancer (GC) is the fifth most common cancer worldwide, with yearly increasing incidence and the second-highest fatality rate in malignancies. Despite the contemporary ambiguous molecular mechanisms in GC pathogenesis, numerous in-depth studies have demonstrated that zinc finger proteins (ZFPs) are essential for the development and progression of GC. ZFPs are a class of transcription factors with finger-like domains that bind to Zn2+ extensively and participate in gene replication, cell differentiation and tumor development. In this review, we briefly outline the roles, molecular mechanisms and the latest advances in ZFPs in GC, including eight principal aspects, such as cell proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis, inflammation and immune infiltration, apoptosis, cell cycle, DNA methylation, cancer stem cells (CSCs) and drug resistance. Intriguingly, the myeloid zinc finger 1 (MZF1) possesses reversely dual roles in GC by promoting tumor proliferation or impeding cancer progression via apoptosis. Therefore, a thorough understanding of the molecular mechanism of ZFPs on GC progression will pave the solid way for screening the potentially effective diagnostic indicators, prognostic biomarkers and therapeutic targets of GC.
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Affiliation(s)
- Shujie Liu
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Xingzhu Liu
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Xin Lin
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
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Ambrozkiewicz F, Trailin A, Červenková L, Vaclavikova R, Hanicinec V, Allah MAO, Palek R, Třeška V, Daum O, Tonar Z, Liška V, Hemminki K. CTNNB1 mutations, TERT polymorphism and CD8+ cell densities in resected hepatocellular carcinoma are associated with longer time to recurrence. BMC Cancer 2022; 22:884. [PMID: 35962322 PMCID: PMC9375422 DOI: 10.1186/s12885-022-09989-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/08/2022] [Indexed: 12/27/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells. Methods Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS). Results TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03–0.52), p = 0.005 for TTR and 0.25 (0.09–0.74), p = 0.01 for DFS. Conclusion The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09989-0.
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Affiliation(s)
- Filip Ambrozkiewicz
- Laboratory of Translational Cancer Genomics, Biomedical Center,Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 323 00, Pilsen, Czech Republic.
| | - Andriy Trailin
- Laboratory of Translational Cancer Genomics, Biomedical Center,Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 323 00, Pilsen, Czech Republic
| | - Lenka Červenková
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.,Department of Pathology, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague, 10, Czech Republic
| | - Radka Vaclavikova
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Toxicogenomics Unit, National Institute of Public Health in Prague, Prague, Czech Republic
| | - Vojtech Hanicinec
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Mohammad Al Obeed Allah
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Richard Palek
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.,Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej 16 Svobody 80, 323 00, Pilsen, Czech Republic
| | - Vladislav Třeška
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej 16 Svobody 80, 323 00, Pilsen, Czech Republic
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic.,Bioptická laboratoř s.r.o., Mikulášské nám, 4, 326 00, Pilsen, Czech Republic
| | - Zbyněk Tonar
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Karlovarska 48, 301 66, Pilsen, Czech Republic.,Laboratory of Quantitative Histology, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 323 00, Pilsen, Czech Republic
| | - Václav Liška
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.,Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Alej 16 Svobody 80, 323 00, Pilsen, Czech Republic
| | - Kari Hemminki
- Laboratory of Translational Cancer Genomics, Biomedical Center,Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, 323 00, Pilsen, Czech Republic.,Department of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
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9
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Yu X, He S, Shen J, Huang Q, Yang P, Huang L, Pu D, Wang L, Li L, Liu J, Liu Z, Zhu L. Tumor vessel normalization and immunotherapy in gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221110176. [PMID: 35872968 PMCID: PMC9297465 DOI: 10.1177/17588359221110176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 06/09/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is a common malignant tumor, and patients with GC have a low survival rate due to limited effective treatment methods. Angiogenesis and immune evasion are two key processes in GC progression, and they act synergistically to promote tumor progression. Tumor vascular normalization has been shown to improve the efficacy of cancer immunotherapy, which in turn may be improved through enhanced immune stimulation. Therefore, it may be interesting to identify synergies between immunomodulatory agents and anti-angiogenic therapies in GC. This strategy aims to normalize the tumor microenvironment through the action of the anti-vascular endothelial growth factor while stimulating the immune response through immunotherapy and prolonging the survival of GC patients.
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Affiliation(s)
- Xianzhe Yu
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Shan He
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Jian Shen
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Qiushi Huang
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Peng Yang
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Lin Huang
- West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Dan Pu
- West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Li Wang
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Lu Li
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Jinghua Liu
- Department of Hepatobiliary Surgery, Linyi People's Hospital, Linyi, Shandong 276000, People's Republic of China
| | - Zelong Liu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lingling Zhu
- Lung Cancer Center, West China Hospital of Sichuan University, No. 37, Guo Xue Xiang, Wuhou District, Chengdu, Sichuan 610041, People's Republic of China
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10
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Čeprnja T, Mrklić I, Perić Balja M, Marušić Z, Blažićević V, Spagnoli GC, Juretić A, Čapkun V, Tečić Vuger A, Vrdoljak E, Tomić S. Prognostic Significance of Lymphocyte Infiltrate Localization in Triple-Negative Breast Cancer. J Pers Med 2022; 12:941. [PMID: 35743725 PMCID: PMC9224650 DOI: 10.3390/jpm12060941] [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: 05/10/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/17/2022] Open
Abstract
High infiltration by tumor-infiltrating lymphocytes (TILs) is associated with favorable prognosis in different tumor types, but the clinical significance of their spatial localization within the tumor microenvironment is debated. To address this issue, we evaluated the accumulation of intratumoral TILs (itTILs) and stromal TILs (sTILs) in samples from 97 patients with early triple-negative breast cancer (TNBC) in the center (sTIL central) and periphery (sTIL peripheral) of tumor tissues. Moreover, the presence of primary and secondary lymphoid aggregates (LAs) and the expression levels of the cancer testis antigen (CTA), NY-ESO-1, and PD-L1 were explored. High infiltration by itTILs was observed in 12/97 samples (12.3%), unrelated to age, Ki67 expression, tumor size, histologic type and grade, and LA presence. NY-ESO-1 was expressed in tumor cells in 37 samples (38%), with a trend suggesting a correlation with itTIL infiltration (p = 0.0531). PD-L1 expression was detected in immune cells in 47 samples (49%) and was correlated with histologic grade, sTILs, and LA formation. The presence of primary LAs was significantly correlated with better disease-free survival (DFS) (p = 0.027). Moreover, no tumor progression was observed during >40 months of clinical follow up in the 12 patients with high itTILs or in the 14 patients with secondary LAs. Thus, careful evaluation of lymphoid infiltrate intratumoral localization might provide important prognostic information.
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Affiliation(s)
- Toni Čeprnja
- Department of Pathology, Forensic Medicine and Cytology, University Hospital Center Split, School of Medicine, University of Split, 21000 Split, Croatia; (I.M.); (S.T.)
| | - Ivana Mrklić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital Center Split, School of Medicine, University of Split, 21000 Split, Croatia; (I.M.); (S.T.)
| | - Melita Perić Balja
- Department of Pathology, University Hospital Center “Sestre Milosrdnice”, 10000 Zagreb, Croatia;
| | - Zlatko Marušić
- Department of Pathology, Zagreb University Hospital Center, 10000 Zagreb, Croatia;
| | | | | | - Antonio Juretić
- Department of Oncology, Clinical Hospital “Sveti Duh”, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Vesna Čapkun
- Department of Nuclear Medicine, University Hospital Centre Split, School of Medicine, University of Split, 21000 Split, Croatia;
| | - Ana Tečić Vuger
- Department of Oncology, University Hospital Center “Sestre Milosrdnice”, 10000 Zagreb, Croatia;
| | - Eduard Vrdoljak
- Department of Oncology, University Hospital Center Split, University of Split, 21000 Split, Croatia;
| | - Snježana Tomić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital Center Split, School of Medicine, University of Split, 21000 Split, Croatia; (I.M.); (S.T.)
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11
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Ma M, Sun J, Liu Z, Ouyang S, Zhang Z, Zeng Z, Li J, Kang W. The Immune Microenvironment in Gastric Cancer: Prognostic Prediction. Front Oncol 2022; 12:836389. [PMID: 35574386 PMCID: PMC9096124 DOI: 10.3389/fonc.2022.836389] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Although therapeutic methods have been developed, gastric cancer (GC) still leads to high rates of mortality and morbidity and is the fourth leading cause of cancer-associated death and the fifth most common cancer worldwide. To understand the factors associated with the prognostic prediction of GC and to discover efficient therapeutic targets, previous studies on tumour pathogenesis have mainly focused on the cancer cells themselves; in recent years, a large number of studies have shown that cancer invasion and metastasis are the results of coevolution between cancer cells and the microenvironment. It seems that studies on the tumour microenvironment could help in prognostic prediction and identify potential targets for treating GC. In this review, we mainly introduce the research progress for prognostic prediction and the immune microenvironment in GC in recent years, focusing on cancer-associated fibroblasts (CAFs), tumour-associated macrophages (TAMs), and tumour-infiltrating lymphocytes (TILs) in GC, and discuss the possibility of new therapeutic targets for GC.
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Affiliation(s)
- Mingwei Ma
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Juan Sun
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zhen Liu
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Siwen Ouyang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zimu Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ziyang Zeng
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Jie Li
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Weiming Kang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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12
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Simsek H, Klotzsch E. The solid tumor microenvironment-Breaking the barrier for T cells: How the solid tumor microenvironment influences T cells: How the solid tumor microenvironment influences T cells. Bioessays 2022; 44:e2100285. [PMID: 35393714 DOI: 10.1002/bies.202100285] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/20/2022]
Abstract
The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies.
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Affiliation(s)
- Hasan Simsek
- Institute for Biology, Experimental Biophysics/Mechanobiology, Humboldt University of Berlin, Berlin, Germany
| | - Enrico Klotzsch
- Institute for Biology, Experimental Biophysics/Mechanobiology, Humboldt University of Berlin, Berlin, Germany.,Laboratory of Applied Mechanobiology, Department for Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
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13
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JAK-STAT1 Signaling Pathway Is an Early Response to Helicobacter pylori Infection and Contributes to Immune Escape and Gastric Carcinogenesis. Int J Mol Sci 2022; 23:ijms23084147. [PMID: 35456965 PMCID: PMC9031264 DOI: 10.3390/ijms23084147] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/22/2022] [Indexed: 01/05/2023] Open
Abstract
Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04-5.30)). We observed that STAT1 was activated in human H. pylori-positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori, we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori-induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer.
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14
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Clinical Efficacy and Adverse Reactions of Bevacizumab plus Radiochemotherapy in the Treatment of Advanced Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:4900037. [PMID: 35178088 PMCID: PMC8847024 DOI: 10.1155/2022/4900037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/22/2021] [Accepted: 12/30/2021] [Indexed: 12/03/2022]
Abstract
Objective To evaluate the clinical efficacy and adverse reactions of bevacizumab plus radiochemotherapy in the treatment of advanced gastric cancer. Methods Eighty-six eligible patients with gastric cancer treated in our institution from August 2019 to August 2020 were recruited and concurrently randomly assigned via the random number table method at a 1 : 1 ratio to receive neoadjuvant radiochemotherapy (control group) or bevacizumab (given on the first day of each course of neoadjuvant radiochemotherapy) plus neoadjuvant radiochemotherapy (study group) for 9 weeks (3 weeks as one course). Outcomes include the clinical efficacy and serum tumor marker levels before and after treatment. Patients in both groups were followed up for 12 months after treatment to obtain progression-free survival (PFS). Assessment of patients' quality of survival was done by the Karnofsky performance score (KPS). The occurrence of adverse reactions in patients during treatment was monitored to evaluate the safety of the treatment protocol. Results The research group outperformed the control group significantly in terms of total treatment efficiency (P < 0.05). After treatment, serum carcinoembryonic antigen (CEA) and glycoantigen 199 (CA199) levels were markedly reduced in both groups, with lower results observed in the research group (P < 0.05). The research group had a significantly longer median PFS than the control group (95% CI: 1.182–2.367, 1.132–2.469, P < 0.05). A significantly higher improvement in quality of survival was observed in the research group than in the control group (P < 0.05). No significant intergroup differences in adverse reactions were reported, and no new safety signals were identified (P > 0.05). Conclusion Bevacizumab potentiates the treatment outcomes for advanced gastric cancer by effectively attenuating the abnormalities of serum tumor marker levels and prolonging survival, with a high safety profile, in combination with radiochemotherapy versus radiochemotherapy alone.
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15
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Wen X, Jin HY, Li M, Kim Y, Cho NY, Kwak Y, Bae JM, Lee HS, Kang GH. Methylation statuses of NCOR2, PARK2, and ZSCAN12 signify densities of tumor-infiltrating lymphocytes in gastric carcinoma. Sci Rep 2022; 12:862. [PMID: 35039565 PMCID: PMC8763922 DOI: 10.1038/s41598-022-04797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/21/2021] [Indexed: 11/29/2022] Open
Abstract
Individual cell types of human tissues have their own CpG site methylation profiles, which might be utilized for the development of methylation markers to denote tumor-infiltrating lymphocytes (TILs). We aimed to develop DNA methylation markers that recapitulate the densities of TILs in gastric carcinoma (GC). Through genome-wide methylation profiling, NCOR2, PARK2, and ZSCAN12 were found to be highly methylated in CD3-positive and CD8-positive cells and rarely methylated in tumor cells. Scores of the three methylation markers were analyzed for their relationship with the overall survival and recurrence-free survival of patients with advanced GC (n = 471). The scores of three methylation markers were closely associated with densities of CD3-positive or CD8-positive cells at the tumor center or invasive front of GCs and found to be a significant prognostic factor in univariate analysis of overall survival and recurrence-free survival. In multivariate analysis, the highest score showed hazard ratios of 0.513 (CI 0.306–0.857) and 0.434 (CI 0.261–0.720) for overall survival and recurrence-free survival, respectively. The findings suggest that methylation markers signifying TILs might be utilized for the recapitulation of TIL density in GCs and serve as biomarkers for predicting prognosis in patients with GC.
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Affiliation(s)
- Xianyu Wen
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye-Yeong Jin
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Meihui Li
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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16
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Miyazaki K, Morine Y, Yamada S, Saito Y, Tokuda K, Okikawa S, Yamashita S, Oya T, Ikemoto T, Imura S, Hu H, Morioka H, Tsuneyama K, Shimada M. Stromal tumor-infiltrating lymphocytes level as a prognostic factor for resected intrahepatic cholangiocarcinoma and its prediction by apparent diffusion coefficient. Int J Clin Oncol 2021; 26:2265-2274. [PMID: 34596803 DOI: 10.1007/s10147-021-02026-3] [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: 05/09/2021] [Accepted: 08/09/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs. METHODS We enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients' clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value. RESULTS Stromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02). CONCLUSIONS Stromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue.
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Affiliation(s)
- Katsuki Miyazaki
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kazunori Tokuda
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shohei Okikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shoko Yamashita
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.,Department of Pathology and Laboratory Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takeshi Oya
- Department of Molecular Pathology, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Satoru Imura
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Haun Hu
- Department of Public Health, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hisayoshi Morioka
- Department of Public Health, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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17
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Olnes MJ, Martinson HA. Recent advances in immune therapies for gastric cancer. Cancer Gene Ther 2021; 28:924-934. [PMID: 33664460 PMCID: PMC8417143 DOI: 10.1038/s41417-021-00310-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/28/2021] [Accepted: 02/11/2021] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is an aggressive malignancy that is the third leading cause of cancer mortality worldwide. Localized GC can be cured with surgery, but most patients present with more advanced non-operable disease. Until recently, treatment options for relapsed and refractory advanced GC have been limited to combination chemotherapy regimens, HER-2 directed therapy, and radiation, which lead to few durable responses. Over the past decade, there have been significant advances in our understanding of the molecular and immune pathogenesis of GC. The infectious agents Epstein-Barr virus and Helicobacter pylori perturb the gastric mucosa immune equilibrium, which creates a microenvironment that favors GC tumorigenesis and evasion of immune surveillance. Insights into immune mechanisms of GC have translated into novel therapeutics, including immune checkpoint inhibitors, which have become a treatment option for select patients with GC. Furthermore, chimeric antigen receptor T-cell therapies have emerged as a breakthrough treatment for many cancers, with recent studies showing this to be a potential therapy for GC. In this review, we summarize the current state of knowledge on immune mechanisms of GC and the status of emerging immunotherapies to treat this aggressive cancer, as well as outline current challenges and directions for future research.
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Affiliation(s)
- Matthew J Olnes
- Hematology and Medical Oncology, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA.
| | - Holly A Martinson
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA
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18
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Challoner BR, von Loga K, Woolston A, Griffiths B, Sivamanoharan N, Semiannikova M, Newey A, Barber LJ, Mansfield D, Hewitt LC, Saito Y, Davarzani N, Starling N, Melcher A, Grabsch HI, Gerlinger M. Computational Image Analysis of T-Cell Infiltrates in Resectable Gastric Cancer: Association with Survival and Molecular Subtypes. J Natl Cancer Inst 2021; 113:88-98. [PMID: 32324860 PMCID: PMC7781469 DOI: 10.1093/jnci/djaa051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/05/2020] [Accepted: 04/02/2020] [Indexed: 01/08/2023] Open
Abstract
Background Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification. Methods Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided. Results CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein–Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs. Conclusion The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC.
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Affiliation(s)
- Benjamin R Challoner
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Katharina von Loga
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Translational Immuno-Oncology Team, Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK
| | - Andrew Woolston
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Beatrice Griffiths
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Nanna Sivamanoharan
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Translational Immuno-Oncology Team, Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK
| | - Maria Semiannikova
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Alice Newey
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Louise J Barber
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - David Mansfield
- Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Lindsay C Hewitt
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands
| | - Yuichi Saito
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
| | - Naser Davarzani
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands.,Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Naureen Starling
- Gastrointestinal Cancer Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Alan Melcher
- Translational Immunotherapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Heike I Grabsch
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands.,Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Marco Gerlinger
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Gastrointestinal Cancer Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
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19
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Díaz Del Arco C, Ortega Medina L, Estrada Muñoz L, García Gómez de Las Heras S, Fernández Aceñero MJ. Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis. Histol Histopathol 2021; 36:587-613. [PMID: 33565601 DOI: 10.14670/hh-18-309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain.
- Complutense University of Madrid, Madrid, Spain
| | - Luis Ortega Medina
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Mª Jesús Fernández Aceñero
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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20
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N J, J T, Sl N, Gt B. Tertiary lymphoid structures and B lymphocytes in cancer prognosis and response to immunotherapies. Oncoimmunology 2021; 10:1900508. [PMID: 33854820 PMCID: PMC8018489 DOI: 10.1080/2162402x.2021.1900508] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tertiary lymphoid structures (TLS) are ectopic cellular aggregates that resemble secondary lymphoid organs in their composition and structural organization. In contrast to secondary lymphoid organs, TLS are not imprinted during embryogenesis but are formed in non-lymphoid tissues in response to local inflammation. TLS structures exhibiting a variable degree of maturation are found in solid tumors. They are composed of various immune cell types including dendritic cells and antigen-specific B and T lymphocytes, that together, actively drive the immune response against tumor development and progression. This review highlights the successive steps leading to tumor TLS formation and its association with clinical outcomes. We discuss the role played by tumor-infiltrating B lymphocytes and plasma cells, their prognostic value in solid tumors and immunotherapeutic responses and their potential for future targeting.
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Affiliation(s)
- Jacquelot N
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Tellier J
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Nutt Sl
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Belz Gt
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia.,The University of Queensland Diamantina Institute, the University of Queensland, Brisbane, Australia
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21
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Li J, Pu K, Li C, Wang Y, Zhou Y. A Novel Six-Gene-Based Prognostic Model Predicts Survival and Clinical Risk Score for Gastric Cancer. Front Genet 2021; 12:615834. [PMID: 33692828 PMCID: PMC7938863 DOI: 10.3389/fgene.2021.615834] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/15/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Autophagy plays a vital role in cancer initiation, malignant progression, and resistance to treatment. However, autophagy-related genes (ARGs) have rarely been analyzed in gastric cancer (GC). The purpose of this study was to analyze ARGs in GC using bioinformatic analysis and to identify new biomarkers for predicting the overall survival (OS) of patients with GC. Methods: The gene expression profiles and clinical data of patients with GC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and ARGs were obtained from two other datasets (the Human Autophagy Database and Molecular Signatures Database). Lasso, univariate, and multivariate Cox regression analyses were performed to identify the OS-related ARGs. Finally, a six-ARG model was identified as a prognostic indicator using the risk-score model, and survival and prognostic performance were analyzed based on the Kaplan-Meier test and ROC curve. Estimate calculations were used to assess the immune status of this model, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed for investigating the functions and terms associated with the model-related genes in GC. Results: The six ARGs, DYNLL1, PGK2, HPR, PLOD2, PHYHIP, and CXCR4, were identified using Lasso and Cox regression analyses. Survival analysis revealed that the OS of GC patients in the high-risk group was significantly lower than that of the low-risk group (p < 0.05). The ROC curves revealed that the risk score model exhibited better prognostic performance with respect to OS. Multivariate Cox regression analysis indicated that the model was an independent predictor of OS and was not affected by most of the clinical traits (p < 0.05). The model-related genes were associated with immune suppression and several biological process terms, such as extracellular structure organization and matrix organization. Moreover, the genes were associated with the P13K-Akt signaling pathway, focal adhesion, and MAPK signaling pathway. Conclusions: This study presents potential prognostic biomarkers for GC patients that would aid in determining the best patient-specific course of treatment.
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Affiliation(s)
- Juan Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, China
| | - Ke Pu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Chunmei Li
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
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22
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Tian C, Jing H, Wang C, Wang W, Cui Y, Chen J, Sha D. Prognostic role of tumour-infiltrating lymphocytes assessed by H&E-stained section in gastric cancer: a systematic review and meta-analysis. BMJ Open 2021; 11:e044163. [PMID: 33518526 PMCID: PMC7853025 DOI: 10.1136/bmjopen-2020-044163] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Some studies have identified tumour-infiltrating lymphocytes (TILs) in H&E-stained sections of gastric cancer, but the prognostic and clinicopathological significance of this remains unclear. The objective of this study is to evaluate the associations between H&E-based TIL density and prognosis and clinicopathological characteristics of patients with gastric cancer. DESIGN Systematic review and meta-analysis. DATA SOURCES Cochrane Library, PubMed and Embase databases were searched through 25 February 2020. ELIGIBILITY CRITERIA Studies evaluating the correlations between TILs assessed by H&E-stained sections and prognosis and clinicopathological characteristics of gastric cancer were included. DATA EXTRACTION AND SYNTHESIS Relevant data were extracted and risks of bias were assessed independently by two reviewers. HR and relative risk (RR) with 95% CI were pooled by random-effect models to estimate the associations between TIL density and overall survival (OS) and clinicopathological characteristics, respectively. RESULTS We enrolled nine studies including 2835 cases for the present meta-analysis. High TILs were associated with superior OS (HR=0.68, 95% CI 0.52 to 0.87, p=0.003) compared with low TILs. High TILs were significantly associated with lower depth of invasion (T3-T4 vs T1-T2) (RR=0.58, 95% CI 0.50 to 0.66, p<0.001), less lymph node involvement (presence vs absence) (RR=0.68, 95% CI 0.56 to 0.81, p<0.001) and earlier TNM (tumour, node, metastasis) stage (III-IV vs I-II) (RR=0.68, 95% CI 0.55 to 0.83, p<0.001). TIL density was not associated with age, gender, Lauren classification or histological grade. The methodology for evaluating TIL and its cut-off value varied across different studies, which might affect the results of our meta-analysis. CONCLUSIONS Our meta-analysis suggests that H&E-based TIL density is a reliable biomarker to predict the clinical outcomes of patients with gastric cancer. Multicentre, prospective studies are needed to further confirm our findings. PROSPERO REGISTRATION NUMBER CRD42020169877.
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Affiliation(s)
- Chunfang Tian
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Haiyan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Caixia Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Weibo Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yangang Cui
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jianpeng Chen
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Dan Sha
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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23
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Attia H, Smyth E. Evolving therapies in advanced oesophago-gastric cancers and the increasing role of immunotherapy. Expert Rev Anticancer Ther 2021; 21:535-546. [PMID: 33349073 DOI: 10.1080/14737140.2021.1866548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Esophagogastric cancers remain a considerable health burden and among the top causes of global cancer-related deaths. Chemotherapy remains the cornerstone of treatment for patients with advanced disease. Doublet platinum/fluoropyrimidine therapy is established as first-line treatment with the option of adding a taxane in selected patients. Irinotecan, taxanes, and ramucirumab are approved as second-line treatments. Results from the trials KEYNOTE-059, ATTRACTION-2, and TAGS have established the use of immune checkpoint inhibitors and trifluridine/tipiracil as a third-line treatment. High PD-L1 expression, microsatellite instability, tumor mutational burden, and Epstein-Barr virus status may also be used to enrich for responses to immunotherapy. AREAS COVERED In this review, we discuss the outcome of recent trials in the later lines of therapy for esophagogastric cancer and place these in the context of current treatment paradigms. We also discuss the biology of esophagogastric cancers and how this might inform the development of new treatments. Finally, we comment on promising new drugs in development. EXPERT OPINION Recent advances in the treatment of chemo-refractory esophagogastric cancer add to the improving survival of patients with this disease. Further research is needed to improve patient selection to therapies and the earlier incorporation of these agents in the treatment journey.
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Affiliation(s)
- Hossameldin Attia
- Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Elizabeth Smyth
- Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
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24
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Cui Y, Li Q, Li W, Wang Y, Lv F, Shi X, Tang Z, Shen Z, Hou Y, Zhang H, Mao B, Liu T. NOTCH3 is a Prognostic Factor and Is Correlated With Immune Tolerance in Gastric Cancer. Front Oncol 2021; 10:574937. [PMID: 33479597 PMCID: PMC7814877 DOI: 10.3389/fonc.2020.574937] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 11/13/2020] [Indexed: 12/28/2022] Open
Abstract
Introduction Although traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC. Methods Formalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures. Results Among the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8+ T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature. Conclusion These findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.
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Affiliation(s)
- Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fang Lv
- Medical Department, Beijing Genecast Biotechnology Co., Beijing, China
| | - Xinying Shi
- Medical Department, Beijing Genecast Biotechnology Co., Beijing, China
| | - Zhaoqing Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Henghui Zhang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Beibei Mao
- Medical Department, Beijing Genecast Biotechnology Co., Beijing, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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25
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Sajjadi E, Venetis K, Scatena C, Fusco N. Biomarkers for precision immunotherapy in the metastatic setting: hope or reality? Ecancermedicalscience 2020; 14:1150. [PMID: 33574895 PMCID: PMC7864694 DOI: 10.3332/ecancer.2020.1150] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
Precision immunotherapy is a crucial approach to improve the efficacy of anti-cancer treatments, particularly in the metastatic setting. In this respect, accurate patient selection takes advantage of the multidimensional integration of patients' clinical information and tumour-specific biomarkers status. Among these biomarkers, programmed death-ligand 1, tumour-infiltrating lymphocytes, microsatellite instability, mismatch repair and tumour mutational burden have been widely investigated. However, novel tumour-specific biomarkers and testing methods will further improve patients' outcomes. Here, we discuss the currently available strategies for the implementation of a precision immunotherapy approach in the clinical management of metastatic solid tumours and highlight future perspectives.
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Affiliation(s)
- Elham Sajjadi
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Konstantinos Venetis
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Cristian Scatena
- Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 57, 56126 Pisa, Italy
| | - Nicola Fusco
- Divison of Pathology, European Institute of Oncology (IEO) IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141 Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
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26
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Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment. Br J Cancer 2020; 124:925-932. [PMID: 33250511 PMCID: PMC7921668 DOI: 10.1038/s41416-020-01188-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 09/25/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
Background The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME). Methods This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3). Results The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73–6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = −0.648, p = 0.005, stromal: r = −0.490, p = 0.046). Conclusions A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.
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27
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Song R, Li Y, Hao W, Yang L, Chen B, Zhao Y, Sun B, Xu F. Circular RNA MTO1 inhibits gastric cancer progression by elevating PAWR via sponging miR-199a-3p. Cell Cycle 2020; 19:3127-3139. [PMID: 33089757 PMCID: PMC7714510 DOI: 10.1080/15384101.2020.1834301] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 08/12/2020] [Accepted: 09/24/2020] [Indexed: 02/03/2023] Open
Abstract
The effect of circular RNA MTO1 (circMTO1) signaling on the expression of miR-199a-3p in gastric carcinoma cells, and its effect on proliferation and apoptosis of gastric cancer cells were investigated in this study. RT-qPCR was performed to detect the expression levels of circMTO1 and miR-199a-3p in the cell lines and tissues of gastric cancer. The effect of circMTO1 and miR-199a-3p on the growth and apoptosis of tumor cells was detected by BrdU incorporation and Annexin V/PI staining. Target gene prediction and screening, and luciferase reporter assays were performed to validate downstream interested genes of circMTO1 and miR-199a-3p. The expression levels of miR-199a-3p target gene PAWR (named as PRKC apoptosis WT1 Regulator Protein) was measured by RT-qPCR and Western blotting. Tumor changes in mice were detected by transfecting circMTO1. The expression of circMTO1 was significantly downregulated in the cell lines and tissues of gastric cancer, and low expression levels of circMTO1 were closely associated with poor prognosis. Overexpression of circMTO1 inhibited tumor growth, enhanced apoptosis rate and decreased cell invasion and migration. There was a significant negative relationship between the expression levels of circMTO1 and miR-199a-3p in gastric cancer tissues. Inhibiting miR-199a-3p expression or overexpression of PAWR could decrease the promotive effects of knockdown of circMTO1 on the progression of gastric cancer, and a positive relationship was established between the expression of circMTO1 and PAWR. circMTO1 can regulate the growth of gastric cancer cells by regulating miR-199a-3p/PAWR axis, thus inhibiting the development and progression of gastric cancer. Abbreviation GC: Gastric cancer; circ RNA: Circular RNA; MTO1: mitochondrial translation optimized 1 homolog.
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Affiliation(s)
- Ruifeng Song
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Ya Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Weiwei Hao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Lei Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Bing Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Yingying Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Binghua Sun
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
| | - Feng Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, PR. China
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Fujimori D, Kinoshita J, Yamaguchi T, Nakamura Y, Gunjigake K, Ohama T, Sato K, Yamamoto M, Tsukamoto T, Nomura S, Ohta T, Fushida S. Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer. BMC Cancer 2020; 20:1014. [PMID: 33081727 PMCID: PMC7574408 DOI: 10.1186/s12885-020-07477-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/30/2020] [Indexed: 01/05/2023] Open
Abstract
Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. Methods Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry. Results The number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P < 0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P < 0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P < 0.05, P < 0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression. Conclusions This model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.
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Affiliation(s)
- Daisuke Fujimori
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Yusuke Nakamura
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Katsuya Gunjigake
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Takashi Ohama
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Koichi Sato
- Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Masami Yamamoto
- Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
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29
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The changing face of gastric cancer: epidemiologic trends and advances in novel therapies. Cancer Gene Ther 2020; 28:390-399. [PMID: 33009508 DOI: 10.1038/s41417-020-00234-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/19/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer is an aggressive solid-tumor malignancy with poor prognosis. The epidemiologic face of gastric cancer is changing and further insight into its heterogenous immunohistopathologic nature is needed to develop personalized therapies for specific patient populations. In this review, we highlight changes in gastric cancer epidemiology with a special emphasis on racial and ethnic variations and discuss the implications of current clinical and preclinical treatment advances.
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30
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Pötzsch M, Berg E, Hummel M, Stein U, von Winterfeld M, Jöhrens K, Rau B, Daum S, Treese C. Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression. Oncoimmunology 2020; 9:1824632. [PMID: 33101772 PMCID: PMC7553533 DOI: 10.1080/2162402x.2020.1824632] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3+, CD4+, or CD8+ TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.
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Affiliation(s)
- M. Pötzsch
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
| | - E. Berg
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
| | - M. Hummel
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- 1.Institute for Pathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - U. Stein
- Experimental and Clinical Research Center, Charité - Universitätsmedizin, Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - M. von Winterfeld
- Institute of Pathology Heidelberg, University Hospital Heidelberg, Germany
| | - K. Jöhrens
- Institute of Pathology, University Carl Gustav Carus, Dresden, Germany
| | - B. Rau
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - S. Daum
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - C. Treese
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
- Experimental and Clinical Research Center, Charité - Universitätsmedizin, Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
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31
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Gao Y, Guo W, Geng X, Zhang Y, Zhang G, Qiu B, Tan F, Xue Q, Gao S, He J. Prognostic value of tumor-infiltrating lymphocytes in esophageal cancer: an updated meta-analysis of 30 studies with 5,122 patients. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:822. [PMID: 32793667 PMCID: PMC7396260 DOI: 10.21037/atm-20-151] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background The prognostic role of tumor-infiltrating lymphocytes (TILs) in esophageal cancer (EC) patients is controversial; therefore, we performed a meta-analysis to obtain a consensus. Methods The PubMed, PubMed Central, Embase, Cochrane Library, and Web of Science databases were searched. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed effect or random effect models depending on the heterogeneity. Results A total of 30 articles comprising 5,122 patients were included in this meta-analysis. High levels of generalized TIL infiltration were associated with better overall survival (OS) (HR =0.67, 95% CI: 0.47–0.95, P=0.02) in EC patients. High CD8+ T-cell infiltration and high CD4+ T-cell infiltration were associated with better OS (HR =0.68, 95% CI: 0.60–0.78, P<0.001; HR =0.70, 95% CI: 0.57–0.85, P<0.001, respectively). However, the pooled results showed that neither CD3+ nor FOXP3+ T-cell infiltration were associated with patient survival (P>0.05). Moreover, for esophageal squamous cell carcinoma (ESCC), high CD8+ T lymphocyte infiltration in the TN (Tumor nest) or TS (Tumor stroma) significantly predicted better OS (pooled HR =0.70, 95% CI: 0.57–0.85; P=0.001; pooled HR =0.77, 95% CI: 0.65–0.91; P=0.003). Conclusions High levels of generalized TILs, high CD8+ T-cell infiltration and high CD4+ T-cell infiltration have the potential to serve as prognostic markers in EC patients. Moreover, high CD8+ TIL in TNs or TS can predict better OS in ESCC patients.
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Affiliation(s)
- Yibo Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Guo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao Geng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yidong Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Big Data Institute, Li Ka Shing Center for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Qiu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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32
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Meier A, Nekolla K, Hewitt LC, Earle S, Yoshikawa T, Oshima T, Miyagi Y, Huss R, Schmidt G, Grabsch HI. Hypothesis-free deep survival learning applied to the tumour microenvironment in gastric cancer. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2020; 6:273-282. [PMID: 32592447 PMCID: PMC7578283 DOI: 10.1002/cjp2.170] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/14/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023]
Abstract
The biological complexity reflected in histology images requires advanced approaches for unbiased prognostication. Machine learning and particularly deep learning methods are increasingly applied in the field of digital pathology. In this study, we propose new ways to predict risk for cancer‐specific death from digital images of immunohistochemically (IHC) stained tissue microarrays (TMAs). Specifically, we evaluated a cohort of 248 gastric cancer patients using convolutional neural networks (CNNs) in an end‐to‐end weakly supervised scheme independent of subjective pathologist input. To account for the time‐to‐event characteristic of the outcome data, we developed new survival models to guide the network training. In addition to the standard H&E staining, we investigated the prognostic value of a panel of immune cell markers (CD8, CD20, CD68) and a proliferation marker (Ki67). Our CNN‐derived risk scores provided additional prognostic value when compared to the gold standard prognostic tool TNM stage. The CNN‐derived risk scores were also shown to be superior when systematically compared to cell density measurements or a CNN score derived from binary 5‐year survival classification, which ignores time‐to‐event. To better understand the underlying biological mechanisms, we qualitatively investigated risk heat maps for each marker which visualised the network output. We identified patterns of biological interest that were related to low risk of cancer‐specific death such as the presence of B‐cell predominated clusters and Ki67 positive sub‐regions and showed that the corresponding risk scores had prognostic value in multivariate Cox regression analyses (Ki67&CD20 risks: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.15–1.89, p = 0.002; CD20&CD68 risks: HR = 1.33, 95% CI = 1.07–1.67, p = 0.009). Our study demonstrates the potential additional value that deep learning in combination with a panel of IHC markers can bring to the field of precision oncology.
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Affiliation(s)
- Armin Meier
- Image Data Sciences, Definiens GmbH, Munich, Germany
| | | | - Lindsay C Hewitt
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Sophie Earle
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's , University of Leeds, Leeds, UK
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Takashi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Ralf Huss
- Institute of Pathology and Molecular Diagnostic, University Hospital Augsburg, Augsburg, Germany
| | | | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.,Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's , University of Leeds, Leeds, UK
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Gastric Inflammatory Prognostic Index (GIPI) in Patients with Metastatic Gastro-Esophageal Junction/Gastric Cancer Treated with PD-1/PD-L1 Immune Checkpoint Inhibitors. Target Oncol 2020; 15:327-336. [DOI: 10.1007/s11523-020-00723-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Mao M, Yu Q, Huang R, Lu Y, Wang Z, Liao L. Stromal score as a prognostic factor in primary gastric cancer and close association with tumor immune microenvironment. Cancer Med 2020; 9:4980-4990. [PMID: 32432377 PMCID: PMC7367639 DOI: 10.1002/cam4.2801] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/15/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Gastric cancer remains one of the major causes for tumor‐related deaths worldwide. Our study aimed to provide an understanding of primary gastric cancer and prompt its clinical diagnosis and treatment. Methods We integrated the expression profiles and overall survival information of primary gastric cancer in TCGA and GEO database and estimated the stromal score of each sample by the estimate R package. Stromal score and clinicopathologic characteristics associated with overall survival were analyzed by using Cox regression and the Kaplan‐Meier method. Gene set enrichment analysis (GSEA) and KEGG analysis were performed to explore the potential molecular mechanism in TCGA dataset. The relationship between immunotherapy‐associated markers or immune cell types and stromal score was explored by using Pearson correlation analysis. Results A total of 796 samples were collected for the analysis. Patients with stromal score‐high showed poor overall survival (P < .01, HR: 1.407, 95% CI: 1.144‐1.731) and identified as an independent prognostic factor. KEGG analysis revealed that stromal score actively involved in diverse tumor‐associated pathways. GSEA analysis also revealed stromal score associated with diverse immune‐related biological processes. Furthermore, stromal score was related with immunotherapy‐associated markers and multiple immune cells. Conclusion Our results showed that stromal score could serve as a potential prognostic biomarker in primary gastric cancer and play an important role in the recognition, surveillance, and prognosis of gastric cancer.
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Affiliation(s)
- Min Mao
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Qingliang Yu
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Rongzhi Huang
- Department of Orthopedic Surgery, The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou First People's Hospital, Qinzhou, China
| | - Yunxin Lu
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Zhen Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liang Liao
- Department of Traumatic Orthopedics and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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35
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Kim Y, Rhee YY, Wen X, Cho NY, Bae JM, Kim WH, Kang GH. Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer. Gastric Cancer 2020; 23:464-472. [PMID: 31691036 DOI: 10.1007/s10120-019-01025-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND High density of tumor-infiltrating lymphocyte (TIL) is known to be associated with prolonged survival time, whereas tumoral-L1 hypomethylation has been associated with shortened survival time in patients with gastric cancer (GC). Since L1-methylation level is high in lymphocytes, higher density of TIL could lead to higher measurement of L1-methylation level in cancer tissues which contain cancer cells as well as non-neoplastic cells, including TIL. Putative interaction of TIL in the relationship between L1-methylation level and survival led us to explore combinatory statuses of tumoral-L1-methylation level and TIL density as a prognostic marker in GC. METHODS TIL and tumoral-L1-methylation level were measured in advanced GC samples (n = 491), using CD3 immunohistochemistry and pyrosequencing-methylation analysis, respectively. TIL density was measured in tumor center and invasive front areas. RESULTS TIL density correlated with tumoral-L1-methylation level but the relationship was weak. Combinatory statuses of L1-methylation level and CD3 TIL density were found to be statistically significant in survival analysis. Multivariate analysis revealed that the relationship between combinatory statuses and survival was independent. Prognostic value of the combinatory statuses at invasive front was significant in an independent set. CONCLUSIONS Our findings indicate that tumoral-L1-methylation level is correlated with TIL density and that combinatory statuses might help to find a subset of GCs with worse clinical outcome in GCs with low-L1-methylation status or a subset of GCs with better clinical outcome in GCs with high-L1-methylation status.
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Affiliation(s)
- Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ye-Young Rhee
- Pathology Center, Seegene Medical Foundation, Seoul, Korea
| | - Xianyu Wen
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. .,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Gambardella V, Castillo J, Tarazona N, Gimeno-Valiente F, Martínez-Ciarpaglini C, Cabeza-Segura M, Roselló S, Roda D, Huerta M, Cervantes A, Fleitas T. The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target. Cancer Treat Rev 2020; 86:102015. [PMID: 32248000 DOI: 10.1016/j.ctrv.2020.102015] [Citation(s) in RCA: 205] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) represents the fifth cause of cancer-related death worldwide. Molecular biology has become a central area of research in GC and there are currently at least three major classifications available to elucidate the mechanisms that drive GC oncogenesis. Further, tumor microenvironment seems to play a crucial role, and tumor-associated macrophages (TAMs) are emerging as key players in GC development. TAMs are cells derived from circulating chemokine- receptor-type 2 (CCR2) inflammatory monocytes in blood and can be divided into two main types, M1 and M2 TAMs. M2 TAMs play an important role in tumor progression, promoting a pro-angiogenic and immunosuppressive signal in the tumor. The diffuse GC subtype, in particular, seems to be strongly characterized by an immuno-suppressive and pro-angiogenic phenotype. No molecular targets in this subgroup have yet been identified. There is an urgent need to understand the molecular pathways and tumor microenvironment features in the GC molecular subtypes. The role of anti-angiogenics and checkpoint inhibitors has recently been clinically validated in GC. Both ramucirumab, a fully humanized IgG1 monoclonal anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, and checkpoint inhibitors in Epstein Bar Virus (EBV) and Microsatellite Instable (MSI) subtypes, have proved beneficial in advanced GC. Nevertheless, there is a need to identify predictive markers of response to anti-angiogenics and immunotherapy in clinical practice for a personalized treatment approach. The importance of M2 TAMs in development of solid tumors is currently gaining increasing interest. In this literature review we analyze immune microenvironment composition and signaling related to M1 and M2 TAMs in GC as well as its potential role as a therapeutic target.
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Affiliation(s)
- V Gambardella
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - J Castillo
- Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - N Tarazona
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - F Gimeno-Valiente
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - C Martínez-Ciarpaglini
- Instituto de Salud Carlos III, CIBERONC, Madrid, Spain; Department of Pathology, INCLIVA Biomedical Research Institute, Spain
| | - M Cabeza-Segura
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - S Roselló
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - D Roda
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - M Huerta
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - A Cervantes
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain
| | - T Fleitas
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; Instituto de Salud Carlos III, CIBERONC, Madrid, Spain.
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37
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Uppal A, Dehal A, Chang SC, Barrak D, Naeini Y, Jalas JR, Bilchik AJ. The Immune Microenvironment Impacts Survival in Western Patients with Gastric Adenocarcinoma. J Gastrointest Surg 2020; 24:28-38. [PMID: 31625020 DOI: 10.1007/s11605-019-04403-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 09/07/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Expression of CD3+ T cells, CD8+ cytotoxic T cells, CD45RO+ memory T cells, and FOXP3+ regulatory T cells at the invasive margin (IM) and tumor center (TC) has correlated with survival in gastric adenocarcinoma (GA) patients from East Asia, independent of anatomic staging. The reason for improved survival in East Asians compared with Western patients is a subject of debate. This study examined the immune profiles of a cohort of Western patients with GA, and their association with overall survival (OS). METHODS Immunohistochemistry (IHC) using antibodies to CD3, CD4, CD8, CD45RO, and FOXP3 was performed on a randomly selected resected GA specimens from 88 Western patients. Cutoffs for high or low expression of each marker were determined with maximally selected rank statistics, and multivariable Cox proportional-hazards models constructed to evaluate the relationship between OS and expression of each marker at the IM and TC. RESULTS Immune cell density was independent of anatomic staging. High expression of CD3, CD4, CD8, and CD45RO at the IM along with CD4 and FOXP3 at the TC were associated with improved OS. A combined marker of CD3, CD8, CD45RO, and FOXP3 associated with OS in East Asian GA was also validated. DISCUSSION This is the first report in US patients to demonstrate that high expression of multiple subsets of T lymphocytes in GA is associated with better OS independent of clinical factors and anatomic stage. Further evaluation of immune-modulating mechanisms may explain survival differences between Western and Eastern patients and provide opportunity for novel treatments.
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Affiliation(s)
- Abhineet Uppal
- Department of Surgical Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
| | - Ahmed Dehal
- Department of Surgical Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA
| | - Shu-Ching Chang
- Medical Data Research Center, Providence St. Joseph Health, Portland, OR, USA
| | - Dany Barrak
- Department of Surgery, Georgetown University Hospital, Washington, DC, USA
| | - Yalda Naeini
- Department of Pathology, Providence St. John's Medical Center, Santa Monica, CA, USA
| | - John R Jalas
- Department of Pathology, Providence St. John's Medical Center, Santa Monica, CA, USA
| | - Anton J Bilchik
- Department of Surgical Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, USA.
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38
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Buettner N, Thimme R. Toward a Better Understanding of Hepatocellular Carcinoma Immune Infiltrates. Cell Mol Gastroenterol Hepatol 2019; 9:341-342. [PMID: 31821781 PMCID: PMC6997445 DOI: 10.1016/j.jcmgh.2019.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/15/2019] [Accepted: 11/15/2019] [Indexed: 02/08/2023]
Affiliation(s)
| | - Robert Thimme
- Correspondence Address correspondence to: Robert Thimme, Medical Center University of Freiburg, Department of Medicine II, Hugstetter Str. 55, D-79106 Freiburg, Germany. fax: +49 761 270 36100.
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39
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Castaneda CA, Castillo M, Aliaga K, Bernabe LA, Casavilca S, Sanchez J, Torres-Cabala CA, Gomez HL, Mas L, Dunstan J, Cotrina JM, Abugattas J, Chavez I, Ruiz E, Montenegro P, Rojas V, Orrego E, Galvez-Nino M, Felix B, Landa-Baella MP, Vidaurre T, Villa MR, Zevallos R, Taxa L, Guerra H. Level of tumor-infiltrating lymphocytes and density of infiltrating immune cells in different malignancies. Biomark Med 2019; 13:1481-1491. [DOI: 10.2217/bmm-2019-0178] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Aim: To correlate levels of tumor-infiltrating lymphocytes (TIL) evaluated using the International Immuno-Oncology Biomarker Working Group methodology, and both density of tumor-infiltrating immune cell and clinicopathological features in different malignancies. Methods: 209 pathological samples from gastric cancer, cervical cancer (CC), non-small-lung cancer, cutaneous melanoma (CM) and glioblastoma were tested for TIL in hematoxylin eosin, and density of CD3+, CD4+, CD8+, CD20+, CD68+ and CD163+ cells by digital analysis. Results: TIL levels were higher in invasive margin compartments (IMC). TIL in IMC, intratumoral and stromal compartments predicted survival. CC and gastric cancer had higher TIL in intratumoral; CC and CM had higher TIL in stromal compartment and IMC. CM had the highest density of lymphocyte and macrophage populations. CD20 density was associated with survival in the whole series. Conclusion: Standardized evaluation of TIL levels may provide valuable prognostic information in a spectrum of different malignancies.
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Affiliation(s)
- Carlos A Castaneda
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
- Faculty of Health Sciences, Universidad Científica del Sur, Lima 15067, Peru
| | - Miluska Castillo
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Karina Aliaga
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis A Bernabe
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Sandro Casavilca
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Joselyn Sanchez
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Carlos A Torres-Cabala
- Departments of Pathology & Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Henry L Gomez
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis Mas
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jorge Dunstan
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jose M Cotrina
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Julio Abugattas
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Ivan Chavez
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Eloy Ruiz
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Paola Montenegro
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Victor Rojas
- Department of Chest Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Enrique Orrego
- Department of Neurosurgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Marco Galvez-Nino
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Brayam Felix
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Maria P Landa-Baella
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Tatiana Vidaurre
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Maria R Villa
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Rocio Zevallos
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis Taxa
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Henry Guerra
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
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Gasenko E, Isajevs S, Camargo MC, Offerhaus GJA, Polaka I, Gulley ML, Skapars R, Sivins A, Kojalo I, Kirsners A, Santare D, Pavlova J, Sjomina O, Liepina E, Tzivian L, Rabkin CS, Leja M. Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia. Eur J Gastroenterol Hepatol 2019; 31:1328-1333. [PMID: 31569122 PMCID: PMC8560222 DOI: 10.1097/meg.0000000000001521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival. METHODS Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009-2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients. RESULTS There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19-0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67-4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72-17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors. CONCLUSION Tumor EBV positivity is a favorable prognostic factor in gastric cancer.
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Affiliation(s)
- Evita Gasenko
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Sergejs Isajevs
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
- Academic Histology Laboratory, Riga, Latvia
| | - M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Inese Polaka
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Institute of Information Technology, Riga Technical University, Riga, Latvia
| | - Margaret L. Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Roberts Skapars
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Armands Sivins
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Ilona Kojalo
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Arnis Kirsners
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
- Institute of Information Technology, Riga Technical University, Riga, Latvia
| | - Daiga Santare
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Jelizaveta Pavlova
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Olga Sjomina
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Elina Liepina
- Riga East University Hospital, Riga, Latvia
- The Centre of Disease Prevention and Control of Latvia, Riga, Latvia
| | - Liliana Tzivian
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
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Kwak Y, Seo AN, Lee HE, Lee HS. Tumor immune response and immunotherapy in gastric cancer. J Pathol Transl Med 2019; 54:20-33. [PMID: 31674166 PMCID: PMC6986974 DOI: 10.4132/jptm.2019.10.08] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023] Open
Abstract
Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.
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Affiliation(s)
- Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Hee Eun Lee
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
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42
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Vihervuori H, Autere TA, Repo H, Kurki S, Kallio L, Lintunen MM, Talvinen K, Kronqvist P. Tumor-infiltrating lymphocytes and CD8 + T cells predict survival of triple-negative breast cancer. J Cancer Res Clin Oncol 2019; 145:3105-3114. [PMID: 31562550 PMCID: PMC6861359 DOI: 10.1007/s00432-019-03036-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 09/19/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE Tumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation. METHODS TNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays. RESULTS Deficiency of stromal TILs and low number of CD8+ T cells independently predicted mortality in TNBC (HR 2.4, p 0.02 and HR 2.1, p 0.02, respectively). Each 10% decrease in stromal TILs resulted in 20% increased risk of mortality. An average of 13.2-year survival difference was observed between the majority (> 75%) of patients with low (< 14% of TILs) vs high (≥ 14% of TILs) frequency of CD8+ T cells. The prognostic value of TILs and CD8+ T cells varied when evaluated in different tumor compartments. TILs and CD8+ T cells were significantly associated with Securin and Separase, essential regulators of metaphase-anaphase transition of the cell cycle. DISCUSSION TILs and CD8+ T cells provide additional prognostic value to the established clinical prognostic markers in TNBC. However, possible clinical applications would still benefit from systematic guidelines for evaluating tumor inflammatory response. Increasing understanding on the interactions between the regulation of cancer cell proliferation and inflammatory response may in future advance treatment of TNBC.
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Affiliation(s)
- H Vihervuori
- Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.
| | - T A Autere
- Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - H Repo
- Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - S Kurki
- Auria Biobank, Turku, Finland
| | | | - M M Lintunen
- Department of Pathology, Turku University Hospital, Turku, Finland
| | - K Talvinen
- Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - P Kronqvist
- Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.,Department of Pathology, Turku University Hospital, Turku, Finland
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Gastric Cancer in the Era of Immune Checkpoint Blockade. JOURNAL OF ONCOLOGY 2019; 2019:1079710. [PMID: 31662748 PMCID: PMC6778883 DOI: 10.1155/2019/1079710] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)‐exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.
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Radiotherapy-Induced Changes in the Systemic Immune and Inflammation Parameters of Head and Neck Cancer Patients. Cancers (Basel) 2019; 11:cancers11091324. [PMID: 31500214 PMCID: PMC6770727 DOI: 10.3390/cancers11091324] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/16/2019] [Accepted: 08/27/2019] [Indexed: 12/24/2022] Open
Abstract
Though radiotherapy is a local therapy, it has systemic effects mainly influencing immune and inflammation processes. This has important consequences in the long-term prognosis and therapy individualization. Our objective was to investigate immune and inflammation-related changes in the peripheral blood of head and neck cancer patients treated with radiotherapy. Peripheral blood cells, plasma and blood cell-derived RNA were isolated from 23 patients before and at two time points after radiotherapy and cellular immune parameters, plasma protein changes and gene expression alterations were studied. Increased regulatory T cells and increased CTLA4 and PD-1 expression on CD4 cells indicated an immune suppression induced by the malignant condition, which was accentuated by radiotherapy. Circulating dendritic cells were strongly elevated before treatment and were not affected by radiotherapy. Decreased endoglin levels in the plasma of patients before treatment were further decreased by radiotherapy. Expression of the FXDR, SESN1, GADD45, DDB2 and MDM2 radiation-response genes were altered in the peripheral blood cells of patients after radiotherapy. All changes were long-lasting, detectable one month after radiotherapy. In conclusion we demonstrated radiotherapy-induced changes in systemic immune parameters of head and neck cancer patients and proposed markers suitable for patient stratification worth investigating in larger patient cohorts.
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45
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Di Blasi D, Boldanova T, Mori L, Terracciano L, Heim MH, De Libero G. Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2019; 9:195-218. [PMID: 31445190 PMCID: PMC6957799 DOI: 10.1016/j.jcmgh.2019.08.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The characterization of T cells infiltrating hepatocellular carcinoma (HCC) provides information on cancer immunity and also on selection of patients with precise indication of immunotherapy. The aim of the study was to characterize T-cell populations within tumor tissue and compare them with non-neoplastic liver tissue as well as circulating cells of the same patients. METHODS The presence of unique cell populations was investigated in 36 HCC patients by multidimensional flow cytometry followed by t-distributed stochastic neighbor embedding analysis. Functional activity of tumor-infiltrating T cells was determined after activation by phorbol 12-myristate 13-acetate and ionomycin. RESULTS Within the tumor there were more cells expressing CD137 and ICOS than in non-neoplastic liver tissue, possibly after recent antigenic activation. These cells contained several populations, including the following: (1) functionally impaired, proliferating CD4+ cells co-expressing Inducible T-cell costimulator (ICOS) and T cell immunoreceptor with Ig and ITIM domains (TIGIT); (2) functionally active CD8+ cells co-expressing CD38 and Programmed cell-death protein 1 (PD1); and (3) CD4-CD8 double-negative T-cell receptor αβ and γδ cells (both non-major histocompatibility complex-restricted T cells). When the identified clusters were compared with histologic classification performed on the same samples, an accumulation of activated T cells was observed in immune-inflamed HCC. The same analyses performed in 7 patients receiving nivolumab treatment showed a remarkable reduction in the functionally impaired CD4+ cells, which returned to almost normal activity over time. CONCLUSIONS Unique populations of activated T cells are present in HCC tissue, whose antigen specificity remains to be investigated. Some of these cell populations are functionally impaired and nivolumab treatment restores their responsiveness. The finding of ongoing immune response within the tumor shows which lymphocyte populations are impaired within the HCC and identifies the patients who might take benefit from immunotherapy.
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Affiliation(s)
- Daniela Di Blasi
- Experimental Immunology, Department of Biomedicine, University of Basel, Switzerland,Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland
| | - Tujana Boldanova
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland,Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - Lucia Mori
- Experimental Immunology, Department of Biomedicine, University of Basel, Switzerland
| | - Luigi Terracciano
- Institute of Pathology, Division of Molecular Pathology, University Hospital Basel, Basel, Switzerland
| | - Markus H. Heim
- Hepatology Laboratory, Department of Biomedicine, University of Basel, Switzerland,Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland,Correspondence Address correspondence to: Gennaro De Libero, MD, or Markus H. Heim, MD, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland. fax: +41 61 265 23 50.
| | - Gennaro De Libero
- Experimental Immunology, Department of Biomedicine, University of Basel, Switzerland,Correspondence Address correspondence to: Gennaro De Libero, MD, or Markus H. Heim, MD, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland. fax: +41 61 265 23 50.
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46
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Wagner DC, Roth W. [Prognostic significance of immune cell infiltrates in tumor pathology]. DER PATHOLOGE 2019; 39:532-538. [PMID: 30350175 DOI: 10.1007/s00292-018-0541-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND The quantity, distribution, activation status, cytokine profile, and spatial distribution of tumor-infiltrating immune cells have prognostic value and may be predictive of response to immunotherapies. OBJECTIVES A survey of relevant immune cell populations including their prognostic significance in the most common types of tumors. METHODS Nonsystematic assessment and a discussion of studies that were conducted to estimate the prognostic significance of certain immune cell subsets and the methodical approaches used. RESULTS For many tumor entities, prognostically favorable and unfavorable immune cell populations can be differentiated. However, nonspecific cell markers that may partly summarize antithetic immune cell subsets can be employed. Differences in sampling procedures and the determination of cut-off levels further limit the comparability of the studies carried out so far. CONCLUSION The phenotypic and functional heterogeneity of tumor-infiltrating immune cells requires the use of cell subset-specific antibodies and antibody combinations. Furthermore, harmonized assessment routines, validation studies, and meta-analyses are important prerequisites for potential diagnostic implementation.
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Affiliation(s)
- D-C Wagner
- Institut für Pathologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Deutschland.
| | - W Roth
- Institut für Pathologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Deutschland
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Kool R, João Mansure J, Kassouf W. Molecular subtyping, tumor infiltration, and trimodal therapy for muscle-invasive bladder cancer: more questions than answers. Transl Androl Urol 2019; 8:S325-S328. [PMID: 31392159 DOI: 10.21037/tau.2019.05.12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Ronald Kool
- Experimental Surgery, McGill University Health Centre, Montreal, Canada
| | - José João Mansure
- Experimental Surgery, McGill University Health Centre, Montreal, Canada
| | - Wassim Kassouf
- Department of Urology, McGill University Health Centre, McGill University, Montreal, Canada
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48
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Chen DD, Cheng JT, Chandoo A, Sun XW, Zhang L, Lu MD, Sun WJ, Huang YP. microRNA-33a prevents epithelial-mesenchymal transition, invasion, and metastasis of gastric cancer cells through the Snail/Slug pathway. Am J Physiol Gastrointest Liver Physiol 2019; 317:G147-G160. [PMID: 30943047 DOI: 10.1152/ajpgi.00284.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Invasion and metastasis are responsible for the majority of deaths in gastric cancer (GC). microRNA-33a (miR-33a) might function as a tumor suppressor in multiple cancers. Here, we describe the regulation and function of miR-33a in GC and mechanisms involved in epithelial-mesenchymal transition (EMT) and metastasis. First, GC tissues and adjacent normal tissues were collected. miR-33a upregulation or SNAI2 depletion on GC cells were introduced to assess the detailed regulatory mechanism of them. We assessed the expression of miR-33a, SNAI2, Snail/Slug signaling pathway-related genes, and EMT-related markers in GC tissues and cells. miR-33a distribution in GC tissues and adjacent normal tissues was measured. Cell proliferation, migration and invasion, and cell cycle distribution were assessed. In nude mice, GC tumor growth and lymph node metastasis were observed. Furthermore, the predicative value of miR-33a in the prognosis of GC patients was evaluated. The obtained results indicated that lowly expressed miR-33a, highly expressed SNAI2, activated Snail/Slug, and increased EMT were identified in GC tissues. miR-33a was located mainly in the cytoplasm. miR-33a targeted and negatively regulated SNAI2. MKN-45 and MKN-28 cell lines were selected for in vitro experiments. Upregulated miR-33a expression or siRNA-mediated silencing of SNAI2 suppressed the activation of Snail/Slug, whereby GC cell proliferation, invasion and migration, EMT, tumor growth, and lymph node metastasis were inhibited. High expression of miR-33a was a protective factor influencing the prognosis of GC. This study suggests that miR-33a inhibited EMT, invasion, and metastasis of GC through the Snail/Slug signaling pathway by modulating SNAI2 expression.NEW & NOTEWORTHY miR-33a targets and inhibits the expression of SNAI2, overexpression of SNAI2 activates the Snail/Slug signaling pathway, the Snail/Slug signaling pathway promotes GC cell proliferation, invasion, and metastasis, and overexpression of miR-33a inhibits cell proliferation, invasion, and metastasis. This study provides a new therapeutic target for the treatment of GC.
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Affiliation(s)
- Di-Di Chen
- Department of Radiotherapy and Chemotherapy, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | | | - Arvine Chandoo
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiang-Wei Sun
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Zhang
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Dong Lu
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei-Jian Sun
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ying-Peng Huang
- Department of General Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Liu JY, Yang GF, Chen FF, Peng CW. Evaluating the prognostic significance of tumor-infiltrating lymphocytes in solid tumor: practice of a standardized method from the International Immuno-Oncology Biomarkers Working Group. Cancer Manag Res 2019; 11:6815-6827. [PMID: 31440080 PMCID: PMC6664256 DOI: 10.2147/cmar.s201538] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/06/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose Tumor-infiltrating lymphocytes (TILs) become increasingly relevant to tumor progression. This study aims to evaluate (a) methods of TILs assessment and (b) their prognostic significance in gastric cancer (GC). Methods The percentage of stromal TILs (psTIL) was reported semi-quantitatively by H&E evaluation. Herein, we screened two independent cohorts of breast cancer (n=240) and GC (n=481) for psTIL characterization. Correlations between psTIL and clinic-pathological features, as well as overall survival (OS) were further explored. Additionally, the prediction role of psTIL in GC was evaluated by receiver operating characteristic curve (ROC) analysis. Results TILs could be demonstrably distinguished from other stromal areas and surrounding tumor nests according to the assessment method. More importantly, it is reproducible, easily to determine, and quickly performed. In GC, a two-grade scale for psTIL was appropriate to be divided into low and high subgroups by using the median value of 10% as the threshold. High psTIL was correlated with no serosa invasion, earlier TNM stage and better survival state (P<0.05 for all), and identified as a favorable prognostic factor both by univariate (HR: 0.734, P=0.047) and multivariate analyses (HR: 0.722, P=0.030). A beneficial OS of high psTIL was found in a linear manner with increasing TILs infiltrates associated with improved survival by Kaplan–Meier survival curve (P=0.030) and ROC analysis (AUC: 0.432, P=0.012). Conclusion TILs provide a reproducible method for assessment that can potentially be used to guide management. The parameter psTIL could be served as an independent, favorable prognostic factor of GC.
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Affiliation(s)
- Jiu-Yang Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, People's Republic of China
| | - Gui-Fang Yang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, People's Republic of China
| | - Fang-Fang Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, People's Republic of China
| | - Chun-Wei Peng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, People's Republic of China
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Prognostic significance of resident CD103 +CD8 +T cells in human colorectal cancer tissues. Acta Histochem 2019; 121:657-663. [PMID: 31153587 DOI: 10.1016/j.acthis.2019.05.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 05/07/2019] [Accepted: 05/22/2019] [Indexed: 02/07/2023]
Abstract
The prognostic significance and clinical implications of resident CD103+CD8+T cells in human colorectal cancer tissues still remains largely unexplored. In our present study, we aimed to characterize the resident CD8+T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance of resident CD8+T cells in colorectal cancer. We found that the OS rate of the colorectal cancer patients with higher infiltration of CD8+T cells, or with higher numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues was significantly better than that of the patients with lower infiltration of CD8+T cells, or with lower numbers of resident CD103+CD8+T cells, or with higher ratio of CD103+CD8+T cells over total CD8+T cells in cancer tissues, respectively. Moreover, higher infiltration of CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with advanced TNM stage. Higher numbers of resident CD103+CD8+T cells in colorectal cancer tissues were significantly and inversely correlated with distant metastasis status. Higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues was significantly and inversely correlated with age status. The COX model analysis demonstrated that higher infiltration of CD8+T cells, higher numbers of resident CD103+CD8+T cells, or higher ratio of CD103+CD8+T cells over total CD8+T cells in colorectal cancer tissues, could serve as independent prognostic predictors for colorectal cancer patients. Taken together, our present study demonstrated the density of tumor infiltrating CD8+T cells or the numbers of resident CD103+CD8+T cells in colorectal tissues could be used as an important prognostic predictor for this malignancy.
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