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Somatic copy number alterations are predictive of progression-free survival in patients with lung adenocarcinoma undergoing radiotherapy

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Cancer Biology & Medicine 2022年第5期19卷 685-695页

作者： Fan Kou Lei Wu Yan Guo Bailu Zhang Baihui Li Ziqi Huang Xiubao Ren Lili Yang department of immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin 300060China

Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,little is known about whether they are predictive of radiotherapy outcomes.We aimed to understand the prognostic value and biological functions of SCNAs.Methods:We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy.Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response.Our results were validated in 20 patients with lung adenocarcinoma(LUAD)receiving radiotherapy.Results:SCNAs were a better predictor of progression-free survival(PFS)in LUAD(P=0.024)than in lung squamous carcinoma(P=0.18)in patients treated with radiotherapy.Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD.Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels(P=0.022).Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS.Additionally,high SCNA may activate the cell cycle pathway and induce tumorigenesis.Conclusions:SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy,in combination with TNM,with the aim of predicting long-term PFS.Therefore,SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.

关键词： SCNA radiotherapy lung cancer progression-free survival immune infiltration

Relationship of VEGF/VEGFR with immune and cancer cells:staggering or forward?

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Cancer Biology & Medicine 2016年第2期13卷 206-214页

作者： Yu-Ling Li Hua Zhao Xiu-Bao Ren department of biotherapy Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer immunology and biotherapy Research Center of Lung Cancer

Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.

关键词：血管内皮生长因子受体免疫细胞 VEGF 癌细胞树突状细胞血管生成因子分泌途径环境信号

Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

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Cancer Biology & Medicine 2015年第2期12卷 126-139页

作者： Jie-Ying Chen Ya-Nan Cheng Lei Han Feng Wei Wen-Wen Yu Xin-Wei Zhang Shui Cao Jin-Pu Yu department of immunology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy Cancer Molecular Diagnostic Core Laboratory Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy biotherapy Center Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy

Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment of non-small cell lung cancer(NSCLC) patients.Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3 CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios(ORs) for objective response rate(ORR) and hazard ratios(HRs) for progression-free survival(PFS) and overall survival(OS) were calculated.Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval(CI), 0.13-0.35], shorter PFS(HR =1.56; 95% CI, 1.27-1.92), and shorter OS(HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3 CA significantly predicted shorter OS(HR =1.83; 95% CI, 1.05-3.20), showed poor ORR(OR =0.70; 95% CI, 0.22-2.18), and shorter PFS(HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFRTKIs. PIK3 CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3 CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.

关键词：酪氨酸激酶抑制剂非小细胞肺癌 EGFR 患者治疗预测表皮生长因子受体价值

Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies

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Cancer Biology & Medicine 2021年第4期18卷 981-991页

作者： Hua Zhao Hao Wang Qiuru Zhou Xiubao Ren department of immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cancer.In the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers.Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients.It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good prognosis.However,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses.These factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory cells.The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in TLSs.It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies.In this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.

关键词： Tertiary lymphoid structure tumor microenvironment immunotherapy B cells T cells

Exhausted T cells and epigenetic status

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Cancer Biology & Medicine 2020年第4期17卷 923-936页

作者： Ziqing Zeng Feng Wei Xiubao Ren department of immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or tumors.The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine production,and upregulation of multiple inhibitory molecular receptors(e.g.,PD-1,TIM-3,and LAG-3).The intracellular metabolic changes,altered expression of transcription factors,and a unique epigenetic landscape constitute the exhaustion program.Recently,researchers have made progress in understanding exhausted T cells,with the definition and identification of exhausted T cells changing from phenotypebased to being classified at the transcriptional and epigenetic levels.Recent studies have revealed that exhausted T cells can be separated into two subgroups,namely TCF1^(+)PD-1^(+)progenitor-like precursor exhausted cells and TCF1-PD-1^(+)terminally differentiated exhausted T cells.Moreover,the progenitor-like precursor cell population may be a subset of T cells that can respond to immunotherapy.Studies have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic levels.TOX also maintains T cell survival and may affect decisions regarding treatment strategies.In this review,we discuss the latest developments in T cell exhaustion in regards to definitions,subpopulations,development mechanisms,differences in diverse diseases,and treatment prospects for exhausted T cells.Furthermore,we hypothesize that the epigenetic state regulated by TOX might be the key point,which can determine the reversibility of exhaustion and the efficacy of immunotherapy.

关键词： T cell exhaustion TOX tumor immunity epigenetic landscape immunotherapy

Immunosuppressive checkpoint Siglec-15:a vital new piece of the cancer immunotherapy jigsaw puzzle

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Cancer Biology & Medicine 2019年第2期16卷 205-210页

作者： Xiubao Ren department of biotherapy Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin Key Laboratory of Cancer immunology and biotherapy Tianjin’s Clinical Research Center for Cancer

On March 5th, a novel immunosuppressive molecule,Siglec-15, was reported in Nature Medicine by Professor Lieping Chen1. Siglec-15 was reported in a wide variety of tumors. The molecule is not a simple replica of PD-1/PD-L1.Rather, the expressions of Siglec-15 and PD-L1 are mutually exclusive1, suggesting that Siglec-15 antibodies may be effective on tumors that are not responsive to anti-PD-1/PDL1 therapy. Siglec-15 potentially serves as a complementary therapeutic target and offers alternative treatments for many anti-PD-l/PD-Ll therapy unresponsive patients. This discovery generated a huge response.

关键词： cancer immunotherapy

Morphine-3-glucuronide upregulates PD-L1 expression via TLR4 and promotes the immune escape of non-small cell lung cancer

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Cancer Biology & Medicine 2021年第1期18卷 155-171页

作者： Kaiyuan Wang Jian Wang Ting Liu Wenwen Yu Nan Dong Chen Zhang Wenbin Xia Feng Wei Lili Yang Xiubao Ren department of Anesthesiology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of Cancer Biobank Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

关键词： Non-small cell lung cancer TLR4 PD-L1 morphine-3-glucuronide immune escape

The role and its mechanism of intermittent fasting in tumors:friend or foe?

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Cancer Biology & Medicine 2021年第1期18卷 63-73页

作者： Xu Zhao Jing Yang Ruoyu Huang Mengmeng Guo Ya Zhou Lin Xu Special Key Laboratory of Gene Detection and Therapy&Base for Talents in biotherapy of Guizhou Province Zunyi 563000China department of immunology Zunyi Medical UniversityZunyi 563000China

Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circumstance of oncology.Recent research has shown that IF can alter the energy metabolism of tumor cells,thereby inhibiting tumor growth and improving antitumor immune responses.Furthermore,IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments.IF is therefore emerging as a promising approach to clinical cancer treatment.However,the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood.In this article,we review the role of IF in tumorigenesis and tumor therapy,and discuss some scientific problems that remain to be clarified,which might provide some assistance in the application of IF in clinical tumor therapy.

关键词： Intermittent fasting energy metabolism tumor immune escape immunotherapy

The prognostic landscape of genes and infiltrating immune cells in cytokine induced killer cell treated-lung squamous cell carcinoma and adenocarcinoma

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Cancer Biology & Medicine 2021年第4期18卷 1134-1147页

作者： Jian Wang Fan Yang Qian Sun Ziqing Zeng Min Liu Wenwen Yu Peng Zhang Jinpu Yu Lili Yang Xinwei Zhang Xiubao Ren Feng Wei department of immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China Cancer Molecular Diagnostics Core Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.

关键词： NSCLC CIK treatment DFS HLA class II infiltrating immune cells