Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

Daniela Cornelia Lazăr ¹, Mihaela Flavia Avram ², Ioan Romoșan ³, Mărioara Cornianu ⁴, Sorina Tăban ⁴, Adrian Goldiș ⁵

Affiliations

¹ Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy "Victor Babeş", Timişoara 300041, Timiş County, Romania. lazar.daniela@umft.ro.
² Department of Surgery X, 1 Surgery Clinic, University of Medicine and Pharmacy "Victor Babeş", Timişoara 300041, Timiş County, Romania.
³ Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy "Victor Babeş", Timişoara 300041, Timiş County, Romania.
⁴ Department of Pathology, University of Medicine and Pharmacy "Victor Babeş", Timişoara 300041, Timiş County, Romania.
⁵ Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy "Victor Babeş", Timişoara 300041, Timiş County, Romania.

PMID: 30166856
224 References
58 citations

Abstract

Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with different clinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.

Keywords: Gastric cancer; Immune checkpoint inhibitors; Immunotherapy; Prognostic significance; Tumor immune microenvironment.

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TSPAN9 suppresses the chemosensitivity of gastric cancer to 5-fluorouracil by promoting autophagy. Yaoyue Qi, Weiwei Qi, +7 authors, Jing Lv. less Cancer Cell Int, 2020 Jan 09; 20. PMID: 31911756 Free PMC article.
Feedback regulation between phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1 and transforming growth factor β1 and prognostic value in gastric cancer. Qi Shao, Zhi-Ming Chen. World J Gastroenterol, 2020 Jan 15; 26(1). PMID: 31933512 Free PMC article.
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Hypofractionated Irradiation Suppressed the Off-Target Mouse Hepatocarcinoma Growth by Inhibiting Myeloid-Derived Suppressor Cell-Mediated Immune Suppression. Junying Chen, Zeng Wang, +11 authors, Lurong Zhang. less Front Oncol, 2020 Mar 03; 10. PMID: 32117702 Free PMC article.
Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine. Xiangyu Ke, Qingsong Qin, +2 authors, Tianyi Deng, Yueyan Liao, Shou-Jiang Gao. less Cancers (Basel), 2020 Feb 09; 12(2). PMID: 32033497 Free PMC article.
Optimization of perioperative approaches for advanced and late stages of gastric cancer: clinical proposal based on literature evidence, personal experience, and ongoing trials and research. Maneesh Kumarsing Beeharry, Tian Qi Zhang, Wen Tao Liu, Zhu Zheng Gang. World J Surg Oncol, 2020 Mar 11; 18(1). PMID: 32151257 Free PMC article. Review.
Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance. Yong-Cang Wang, Yin Dai, +3 authors, Ge-Liang Xu, Wei Yu, Rui-Liang Quan, Ya-Jun Zhao. less Med Sci Monit, 2020 Mar 29; 26. PMID: 32218416 Free PMC article.
Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis. Jacek Baj, Karolina Brzozowska, +3 authors, Piero Portincasa. less Int J Mol Sci, 2020 Apr 10; 21(7). PMID: 32268527 Free PMC article. Review.
Development and validation of a hypoxia-immune-based microenvironment gene signature for risk stratification in gastric cancer. Yifan Liu, Jianhua Wu, +4 authors, Hao Wang. less J Transl Med, 2020 May 16; 18(1). PMID: 32410620 Free PMC article.
Chemokine receptor 4 expression is correlated with the occurrence and prognosis of gastric cancer. Yang Li, Hong-Chang Wang, +2 authors, Jin-Shen Wang, Bo Sun, Le-Ping Li. less FEBS Open Bio, 2020 Apr 20; 10(6). PMID: 32306562 Free PMC article.
A clinical study of traditional Chinese medicine prolonging the survival of advanced gastric cancer patients by regulating the immunosuppressive cell population: A study protocol for a multicenter, randomized controlled trail. Xiaoting Pan, Heyun Tao, +11 authors, Qingmin Sun. less Medicine (Baltimore), 2020 Apr 22; 99(16). PMID: 32311976 Free PMC article.
Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival. Jingwei Liu, Hao Li, +2 authors, Liping Sun, Yuan Yuan, Chengzhong Xing. less Biomed Res Int, 2020 Jul 01; 2020. PMID: 32596285 Free PMC article.
Stromal score as a prognostic factor in primary gastric cancer and close association with tumor immune microenvironment. Min Mao, Qingliang Yu, +3 authors, Rongzhi Huang, Yunxin Lu, Zhen Wang, Liang Liao. less Cancer Med, 2020 May 21; 9(14). PMID: 32432377 Free PMC article.
CAR-T Cell Therapy-An Overview of Targets in Gastric Cancer. Dominika Bębnowska, Ewelina Grywalska, +6 authors, Wojciech Polkowski. less J Clin Med, 2020 Jun 21; 9(6). PMID: 32560392 Free PMC article. Review.
Identification of an immune-related gene-based signature to predict prognosis of patients with gastric cancer. Xiang-Ting Qiu, Yu-Cui Song, +3 authors, Jian Liu, Zhen-Min Wang, Xing Niu, Jing He. less World J Gastrointest Oncol, 2020 Sep 04; 12(8). PMID: 32879664 Free PMC article.
From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers-A Multidisciplinary Perspective. Giulia Accordino, Sara Lettieri, +10 authors, Giulia Maria Stella. less Cancers (Basel), 2020 Aug 06; 12(8). PMID: 32751137 Free PMC article. Review.
Identification of New Therapeutic Targets for Gastric Cancer With Bioinformatics. Yang Li, Jin-Shen Wang, +2 authors, Tao Zhang, Hong-Chang Wang, Le-Ping Li. less Front Genet, 2020 Oct 06; 11. PMID: 33014013 Free PMC article.
Identification and validation of the prognostic value of immune-related genes in non-small cell lung cancer. Rui Li, Xiao Liu, +4 authors, Yi-Qing Qu. less Am J Transl Res, 2020 Oct 13; 12(9). PMID: 33042464 Free PMC article.
Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets. Na Ren, Bin Liang, Yunhui Li. Biosci Rep, 2020 Oct 06; 40(10). PMID: 33015704 Free PMC article.
Manganese-Based Targeted Nanoparticles for Postoperative Gastric Cancer Monitoring via Magnetic Resonance Imaging. Ke Li, Peng Li, Yang Wang, Shuang Han. Front Oncol, 2020 Nov 17; 10. PMID: 33194769 Free PMC article.
Gastric cancer: a comprehensive review of current and future treatment strategies. Rachel E Sexton, Mohammed Najeeb Al Hallak, Maria Diab, Asfar S Azmi. Cancer Metastasis Rev, 2020 Sep 08; 39(4). PMID: 32894370 Free PMC article. Review.
Exosomal miRNA-16-5p Derived From M1 Macrophages Enhances T Cell-Dependent Immune Response by Regulating PD-L1 in Gastric Cancer. Zhengtian Li, Bing Suo, +6 authors, Dawei Wang. less Front Cell Dev Biol, 2020 Dec 18; 8. PMID: 33330451 Free PMC article.
An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma. Bing Wang, Yang Zhang. Open Med (Wars), 2020 Dec 19; 15(1). PMID: 33336043 Free PMC article.
pH-Sensitive and Long-Circulation Nanoparticles for Near-Infrared Fluorescence Imaging-Monitored and Chemo-Photothermal Synergistic Treatment Against Gastric Cancer. Yun Zhou, Xuanzi Sun, Liansuo Zhou, Xiaozhi Zhang. Front Pharmacol, 2021 Jan 01; 11. PMID: 33381047 Free PMC article.
Prognostic impact of the preoperative hemoglobin A1c levels in patients with gastric cancer surgery depends on postoperative complications. Jun Shibamoto, Katsutoshi Shoda, +14 authors, Eigo Otsuji. less Surg Today, 2020 Aug 11; 51(3). PMID: 32772168 Free PMC article.
Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components. Yongwei Wang, Sen Guo, +3 authors, Zhihong Chen, Bing Bai, Shuo Wang, Yaxian Gao. less Front Oncol, 2021 Mar 02; 10. PMID: 33643909 Free PMC article.
Curcumin inhibits the growth of liver cancer by impairing myeloid-derived suppressor cells in murine tumor tissues. Sha Tian, Liu Liao, +5 authors, Xuefei Tian. less Oncol Lett, 2021 Mar 19; 21(4). PMID: 33732362 Free PMC article.
KMT2D promotes proliferation of gastric cancer cells: evidence from ctDNA sequencing. Qiaolian Li, Riping Wu, Fan Wu, Qiang Chen. J Clin Lab Anal, 2021 Apr 02; 35(4). PMID: 33793001 Free PMC article.
Longnon-coding RNA BLACAT2 promotes gastric cancer progression via the miR-193b-5p/METTL3 pathway. Hao Hu, Qi Kong, +9 authors, Ya-Bin Xia. less J Cancer, 2021 May 13; 12(11). PMID: 33976730 Free PMC article.
CCL21 activation of the MALAT1/SRSF1/mTOR axis underpins the development of gastric carcinoma. Qianmei Fu, Xiaohong Tan, Huaming Tang, Jijiang Liu. J Transl Med, 2021 May 19; 19(1). PMID: 34001131 Free PMC article.
Significance of a preoperative systemic immune-inflammation index as a predictor of postoperative survival outcomes in gastric cancer. Hiroyuki Inoue, Toshiyuki Kosuga, +5 authors, Eigo Otsuji. less World J Surg Oncol, 2021 Jun 14; 19(1). PMID: 34118953 Free PMC article.
A Tumor Progression Related 7-Gene Signature Indicates Prognosis and Tumor Immune Characteristics of Gastric Cancer. Fen Liu, Zongcheng Yang, +5 authors, Yue Fu. less Front Oncol, 2021 Jul 02; 11. PMID: 34195091 Free PMC article.
Immune Cell Infiltration as Signatures for the Diagnosis and Prognosis of Malignant Gynecological Tumors. Qi-Fang Liu, Zi-Yi Feng, +3 authors, Li-Li Jiang, Tong-Tong Xu, Si-Man Li, Kui-Ran Liu. less Front Cell Dev Biol, 2021 Jul 06; 9. PMID: 34222265 Free PMC article.
Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer. Jun-Peng Pei, Chun-Dong Zhang, +2 authors, Maimaititusun Yusupu, Cheng Zhang, Dong-Qiu Dai. less Front Immunol, 2021 Jul 13; 12. PMID: 34249015 Free PMC article.
Immune-Related Nine-MicroRNA Signature for Predicting the Prognosis of Gastric Cancer. Jingxuan Xu, Jian Wen, +5 authors, Yaping Zhao. less Front Genet, 2021 Jul 23; 12. PMID: 34290743 Free PMC article.
Helicobacter pylori promotes gastric cancer progression by upregulating semaphorin 5A expression via ERK/MMP9 signaling. Guoqing Pan, Xianwen Wang, +7 authors, Zi Lei. less Mol Ther Oncolytics, 2021 Sep 14; 22. PMID: 34514104 Free PMC article.
State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer. Debora Basile, Francesca Simionato, +3 authors, Giuseppe Aprile. less Biologics, 2021 Nov 13; 15. PMID: 34764633 Free PMC article. Review.
Comprehensive analysis of prognostic genes in gastric cancer. Shaohua Huang, Liping Ma, +3 authors, Biyang Lan, Ning Liu, Wenwei Nong, Zhihu Huang. less Aging (Albany NY), 2021 Oct 24; 13(20). PMID: 34686626 Free PMC article.
Development and Verification of an Immune-Based Gene Signature for Risk Stratification and Immunotherapeutic Efficacy Assessment in Gastric Cancer. Feng Qiu, Yumei Zhu, +2 authors, Yafeng Shi, Jingjing Ji, Yingchao Jin. less Dis Markers, 2021 Nov 23; 2021. PMID: 34804261 Free PMC article.
Immune landscape of advanced gastric cancer tumor microenvironment identifies immunotherapeutic relevant gene signature. Simeng Zhang, Mengzhu Lv, +3 authors, Yu Cheng, Shuo Wang, Ce Li, Xiujuan Qu. less BMC Cancer, 2021 Dec 12; 21(1). PMID: 34893046 Free PMC article.
Discovery and Validation of Novel Methylation Markers in Helicobacter pylori-Associated Gastric Cancer. Huan Wang, Nian-Shuang Li, +4 authors, Yi Hu. less Dis Markers, 2021 Dec 21; 2021. PMID: 34925643 Free PMC article.
Differentially Expressed Genes in Clear Cell Renal Cell Carcinoma as a Potential Marker for Prognostic and Immune Signatures. Ying Tong, Yiwen Yu, +5 authors, Lin Guo. less Front Oncol, 2022 Jan 04; 11. PMID: 34976818 Free PMC article.
Targeted FGFR/VEGFR/PDGFR inhibition with dovitinib enhances the effects of nab-paclitaxel in preclinical gastric cancer models. Kate Crawford, Erin Bontrager, +7 authors, Niranjan Awasthi. less Cancer Biol Ther, 2021 Dec 10; 22(10-12). PMID: 34882068 Free PMC article.
Long noncoding RNA FAM225A promotes the malignant progression of gastric cancer through the miR-326/PADI2 axis. Xiang Ma, Gang Wang, +9 authors, Li Yang. less Cell Death Discov, 2022 Jan 13; 8(1). PMID: 35017465 Free PMC article.
Gastric cancer cell death analyzed by live cell imaging of spheroids. George Alzeeb, Danielle Arzur, +3 authors, Catherine Le Jossic-Corcos. less Sci Rep, 2022 Jan 29; 12(1). PMID: 35087119 Free PMC article.
Comprehensive analysis on the expression profile and prognostic values of Synaptotagmins (SYTs) family members and their methylation levels in gastric cancer. Mei-Feng Yang, Xing-Xing Long, +7 authors, De-Feng Li. less Bioengineered, 2021 Jul 08; 12(1). PMID: 34229539 Free PMC article.
An artificial intelligence method to assess the tumor microenvironment with treatment outcomes for gastric cancer patients after gastrectomy. Tao Chen, Xunjun Li, +13 authors, Guoxin Li. less J Transl Med, 2022 Feb 23; 20(1). PMID: 35189890 Free PMC article.
Comprehensive Analysis of an Individualized Immune-Related lncRNA Pair Signature in Gastric Cancer. Chuang Nie, Jiabao Zhai, +10 authors, Haibo Zhou. less Front Cell Dev Biol, 2022 Mar 12; 10. PMID: 35273959 Free PMC article.
Comprehensive analysis of tumor immune microenvironment and prognosis of m6A-related lncRNAs in gastric cancer. Yi Wang, Gui-Qi Zhu, +4 authors, Meng-Su Zeng. less BMC Cancer, 2022 Mar 26; 22(1). PMID: 35331183 Free PMC article.
miR-139-3p/Kinesin family member 18B axis suppresses malignant progression of gastric cancer. Hailin Ke, Songling Wu, Yueyi Zhang, Guowei Zhang. Bioengineered, 2022 Feb 10; 13(2). PMID: 35137670 Free PMC article.
Evaluation of Immune Infiltration Based on Image Plus Helps Predict the Prognosis of Stage III Gastric Cancer Patients with Significantly Different Outcomes in Northeastern China. Tianyi Fang, Zhidong Wang, +6 authors, Yingwei Xue. less Dis Markers, 2022 Apr 05; 2022. PMID: 35371344 Free PMC article.
Development of Tumor Mutation Burden-Related Prognostic Model and Novel Biomarker Identification in Stomach Adenocarcinoma. Min Fu, Yongbiao Huang, +9 authors, Guangyuan Hu. less Front Cell Dev Biol, 2022 Apr 12; 10. PMID: 35399509 Free PMC article.
Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma. Ying Guo, Guangyu Zhou, +2 authors, Qingjie Ma, Li Zhang, Jiwei Chen. less Open Life Sci, 2022 Apr 14; 17(1). PMID: 35415241 Free PMC article.

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