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Genes & Diseases 2022年第5期9卷 1208-1219页

作者： Liu Yang Guohong Liu Yirong Li Yunbao Pan Department of Laboratory Medicine Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei 430071PR China Department of Radiology Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei 430071PR China

The clinical study of nasopharyngeal carcinoma(NPC)often reveals a large number of lymphocytes infiltrating the primary tumor *** an important part of the tumor microenvironment,tumor-infiltrating lymphocytes(TILs)do not exist alone but as a complex multicellular population with high *** play an extremely significant role in the occurrence,development,invasion and metastasis of *** latest research shows that they participate in tumorigenesis and treatment,and the composition,quantity,functional status and distribution of TILs subsets have good predictive value for the prognosis of NPC *** are an independent prognostic factor for TNM stage and significantly correlated with better ***,adoptive immunotherapy using anti-tumor TILs has achieved good results in a variety of solid tumors including *** review evaluates recent clinical and preclinical studies of NPC,summarizes the role of TILs in promoting and inhibiting tumor growth,evaluates the predictive value of TILs,and explores the potential benefits of TILs-based immunotherapy in the treatment of NPC.

关键词： Nasopharyngeal carcinoma NPC microenvironment tumor-infiltrating lymphocyte tumor immunotherapy tumor prognosis

Interleukin-18 and -12 synergistically enhance cytotoxic functions of tumor-infiltrating lymphocytes

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Chinese Medical Journal 2012年第23期125卷 4245-4248页

作者： CHEN Zhi-fen ZHOU Rui XIA Bing DENG Chang-sheng Department of Gastroenterology Zhongnan Hospital of Wuhan UniversityWuhanHubei 430071China Clinical Center of Intestinal&Colorectal Diseases of Hubei Province WuhanHubei 430071China Key Laboratory of Intestinal&Colorectal Diseases of Hubei Province WuhanHubei 430071China

Background The role of tumor-infiltrating lymphocytes （TILs） in the immunopathogenesis of individual cancer is not clear and is a challenge for anti-tumor immunotherapy. This study aimed to investigate the effects of interleukin （IL）-18 and -12 on cytotoxic functions of TILs, Methods TILs from postoperative gastric cancer patients were costimulated with IL-18 and IL-12. SGC-7g01 tumor cells were pre-incubated with TILs and subcutaneously injected into BALB/C SCID mice. The function of TILs was evaluated by measuring tumor sizes in tumor-bearing mice, T helper （Th）l （tumor necrosis factor （TNF）-a, interferon （IFN）-y） and Th2 cytokine levels （IL-10 and IL-4） in serum and cytotoxicity of mouse natural killer （NK） and CD8＋ T cells. Results IL-18 and IL-12 synergistically inhibited the growth of SGC-7901 cells in vivo and significantly extended the survival rate of SGC-7901-bearing mice （66.7% vs. 13.7%, P 〈0.01）. Moreover, TILs could promote the secretion of TNF-a and IFN-y （（130.34±7.65） vs. （210.63±12.31） pg/ml, P 〈0.01; （14.23±1.97） vs. （30.52±2.12） pg/ml, P 〈0.01）, and downregulate IL-10 and IL-4 secretion （（103.72±11.21）vs. （61.36±5.41） pg/ml, P=0.021; （49.36±4.67）vs. （28.48±3.86） pg/ml, P=0.024）. Conclusion IL-18 and IL-12 can synergistically enhance cytotoxic functions of TILs from human gastric cancer.

关键词： interleukin-18 interleukin-12 tumor-infiltrating lymphocyte gastric cancer

Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

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World Journal of Clinical Oncology 2024年第7期15卷 920-935页

作者： Hai-Kuan Sun Wen-Long Jiang Shi-Lei Zhang Peng-Cheng Xu Li-Min Wei Jiang-Bo Liu Department of Thyroid and Breast Surgery The First Affiliated HospitalCollege of Clinical MedicineHenan University of Science and TechnologyLuoyang 471000Henan ProvinceChina

BACKGROUND The association between tumor-infiltrating lymphocyte(TIL)levels and the res-ponse to neoadjuvant therapy(NAT)in patients with triple-negative breast cancer(TNBC)remains *** To investigate the predictive potential of TIL levels for the response to NAT in TNBC *** A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31,*** correlation between TIL levels and the NAT pathologic com-plete response(pCR)in TNBC patients was assessed using a systematic review and *** analysis,sensitivity analysis,and publication bias analysis were also *** A total of 32 studies were included in this *** overall meta-ana-lysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup(48.0%vs 27.7%)(risk ratio 2.01;95%confidence interval 1.77-2.29;P<0.001,I2=56%).Subgroup analysis revealed that the between-study hetero-geneity originated from differences in study design,TIL level cutoffs,and study *** bias could have existed in the included *** meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols(all P≤0.01),and there was no significant between-protocol difference in the statistics among the different NAT protocols(P=0.29).Additionally,sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually *** TILs can serve as a predictor of the response to NAT treatment in TNBC *** patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs,and this predictive capability is con-sistent across different NAT regimens.

关键词： Breast cancer tumor-infiltrating lymphocyte Neoadjuvant therapy Treatment response Systematic review Meta-analysis

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8^(+ ) T lymphocytes in human non-small cell lung cancer

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Cellular & Molecular Immunology 2010年第5期7卷 389-395页

作者： Yan Zhang Shengdong Huang Dejun Gong Yanghua Qin Qian Shen Department of Laboratory Diagnosis Changhai HospitalSecond Military Medical UniversityShanghaiChina Institute of Cardiothoracic Surgery Changhai HospitalSecond Military Medical UniversityShanghaiChina

T-cell tolerance is an important mechanism for tumor escape,but the molecular pathways involved in T-cell tolerance remain poorly *** remains unknown whether the inhibitory immunoreceptor programmed death-1(PD-1)plays a role in conditions of human non-small cell lung cancer(NSCLC).In this study,we detected PD-1 expression on CD81 T cells from healthy control peripheral blood mononuclear cells(PBMCs)and the PBMCs of NSCLC patients as well as NSCLC *** showed that tumor-infiltrating CD81 T cells had increased PD-1 expression and impaired immune function,including reducing cytokine production capability and impairing capacity to *** of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell *** data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD81 T-cell dysfunction in NSCLC ***,blocking this pathway provides a potential therapy target in lung cancer.

关键词： lung cancer programmed death-1 tumor-infiltrating lymphocyte

Expression of calreticulin is associated with infiltration of T-cells in stage ⅢB colon cancer

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World Journal of Gastroenterology 2010年第19期16卷 2428-2434页

作者： Rui-Qing Peng, Ya Ding, Xing Zhang, Yi-Xin Zeng, Xiao- Shi Zhang, State Key Laboratory of Oncology in South China, Biotherapy Center, Cancer Center, Sun Yat-Sen University, 651 Dongfeng R E, Guangzhou 510060, Guangdong Province, China Ying-Bo Chen, Zhi-Wei Zhou, State Key Laboratory of Oncology in South China, Department of Gastric and Pancreatic Oncology, Cancer Center, Sun Yat-Sen University, 651 Dongfeng R E, Guangzhou 510060, Guangdong Province, China Rong Zhang, State Key Laboratory of Oncology in South China, Department of Endoscopy, Cancer Center, Sun Yat-Sen University, 651 Dongfeng R E, Guangzhou 510060, Guangdong Province, China Xing-Juan Yu, Yi-Xin Zeng, State Key Laboratory of Oncology in South China, Department of Experimental Research, Cancer Center, Sun Yat-Sen University, 651 Dongfeng R E, Guangzhou 510060, Guangdong Province, China State Key Laboratory of Oncology in South China Biotherapy Center Sun Yat-sen University 651 Dongfeng R E Guangzhou 510060 Guangdong Province China.

AIM: To investigate the correlation between expression of calreticulin and infiltration of lymphocytes in stage ⅢB colon cancer. METHODS: Sixty-eight pathologically-confirmed speci-mens were obtained from stage ⅢB (T3N1M0) colon cancer patients who underwent radical resection between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University, Guangzhou, China. Immuno-histochemical analysis was performed to show infiltration of lymphocytes and expression of calreticulin in colon cancer. Association between calreticulin expression, infiltration of lymphocytes, and 5-year survival rate of patients was assessed. RESULTS: The expression level of calreticulin was lower in cancer nest than in its adjacent normal epithelium since 61.8% (42/68) of the samples were stained with calreticulin in colon cancer. The expression of calreticulin in colon cancer was associated with the infi ltration of CD45RO+ cells rather than with that of CD3+ cells. In addition, the stronger expression of calreticulin and the higher infiltration of CD3+ and CD45RO+ cells in colon cancer were associated with the higher 5-year survival rate of patients. CONCLUSION: Expression of calreticulin is associated with infiltration of T-cells, which implies that a low expression level of molecular marker may represent a new mechanism underlying immune escape in colon cancer.

关键词： Calreticulin tumor-infiltrating lymphocyte Colon cancer Immune escape

Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

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World Journal of Gastroenterology 2018年第20期24卷 2137-2151页

作者： Marc Hilmi Laurent Bartholin Cindy Neuzillet Service d'Oncologie Médicale H?pital Henri Mondor Assistance Publique-H?pitaux de Paris Université Paris Est Créteil Université de Lyon Université Claude Bernard Lyon 1 Inserm U1052 CNRS 5286Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon

Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to *** these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(tumor immunogenicity and promoting the recruitment and activation of effector T *** studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting *** T-cell transfer is also under ***,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

关键词： Drug therapy combination Immunology Hypoxia Checkpoint inhibitor Inflammation Pancreatic cancer tumor-infiltrating lymphocyte Transforming growth factorβ tumor microenvironment

KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer

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Cancer Communications 2022年第9期42卷 828-847页

作者： Chengming Liu Sufei Zheng Zhanyu Wang Sihui Wang Xinfeng Wang Lu Yang Haiyan Xu Zheng Cao Xiaoli Feng Qi Xue Yan Wang Nan Sun Jie He Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Comprehensive Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China

Background:Although immune checkpoint inhibitors(ICIs)against programmed cell death protein 1(PD-1)and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma(NSCLC),the potential association between Kirsten rat sarcoma viral oncogene homolog(KRAS)oncogene substitutions and the efficacy of ICIs remains *** this study,we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance ***:The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort(n=74),and confirmed with a mouse *** addition,the tumor immune microenvironment(TIME)of KRASmutant NSCLC,such as CD8+tumor-infiltrating lymphocytes(TILs)and PD-L1 level,was *** lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of ***,interventions that improved TIME were developed to increase responsiveness to ***:We observed the inferior efficacy of ICIs in KRAS-G12D-mutant *** upon transcriptome data and immunostaining results from KRAS-mutant NSCLC,KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+TILs,which in turn yielded an immunosuppressive *** analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2(HMGA2)***,paclitaxel,a chemotherapeutic agent,upregulated HMGA2 level,and in turn,stimulated the secretion of CXCL10/***,PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung *** analyses revealed that the combined treatment significantly enhanced th

关键词： KRAS-G12D non-small cell lung carcinoma immunotherapy PD-L1 tumor-infiltrating lymphocyte chemo-immunotherapy

Intratumoral CD103^(+)CD8^(+)T cells predict response to neoadjuvant chemoimmunotherapy in advanced head and neck squamous cell carcinoma

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Cancer Communications 2023年第10期43卷 1143-1163页

作者： Siqi Ren Tianjun Lan Fan Wu Suling Chen Xue Jiang Chuying Huo Zitian Li Shule Xie Donghui Wu Ruixin Wang Yanyan Li Lin Qiu Guoxin Huang Shurui Li Xiaojuan Wang Meifeng Cen Tingting Cai Zhaoyu Lin Jinsong Li Bowen Li Department of Oral and Maxillofacial Surgery Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangdongP.R.China Guangdong Provincial Key Laboratory of Malignant tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangdongP.R.China Department of Gynecological Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangdongP.R.China School of Stomatology Jilin UniversityJilinP.R.China Stomatology Hospital of Haizhu district GuangdongP.R.China

Background Immune cell heterogenicity is known to determine the therapeutic response to cancer *** chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is *** efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical ***,we attempted to identify molecules predicting NACI response in advanced *** We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor *** regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC *** We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in *** scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC *** receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to *** assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in ***,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity

关键词： CD103 CD8 head and neck squamous cell carcinoma neoadjuvant chemoimmunotherapy predictive marker tumor-infiltrating lymphocyte

Analysis of CD8＋ Treg cells in patients with ovarian cancer： a possible mechanism for immune impairment

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Cellular & Molecular Immunology 2015年第5期12卷 580-591页

作者： Shuping Zhang Department of Laboratory Medicine the First Affiliated Hospital of Nanjing Medical University Nanjing China National Key Clinical Department of Laboratory Medicine Nanjing China Department of Obstetrics and Gynecology Southwest Hospital Third Military Medical University Chongqing China Department of Obstetrics and Gynecology Jinling Hospital Nanjing University School of Medicine Nanjing China

Regulatory T （Treg） cells may participate in mediating a suppressive microenvironment that blunts successful anti-tumor immunotherapy. Recent studies show that CD8＋ Treg cells might impede effective immune responses to established tumors. However, there is limited research regarding CD8＋ Treg cells in ovarian cancer （OC） patients. Here, we investigated CD8＋ Treg cells in OC patients and their in vitro induction. The immunohistochemistry of tumor-infiltrating lymphocytes revealed a significant correlation between the intratumoral CD8＋ T cells and the forkhead box p3 （Foxp3）＋ cells in the intraepithelial and stromal areas of advanced OC tissues. We examined the expression of Treg markers in CD8＋ T cells from the peripheral blood and fresh tumor tissues of OC patients using flow cytometry. Our results indicated an increase in the CD8＋ Treg cell subsets of OC patients compared with those in patients with benign ovarian tumors and healthy controls, including a n increased expression of CD25, cytotoxic T-lymphocyte-associated protein 4 （CTLA-4）, and Foxp3 and decreased CD28 expression. To demonstrate whether the tumor microenvironment could convert CD8＋ effector T cells into suppressor cells, we used an in vitro transwell culturing system. Compared with the CD8＋ T cells cultured alone, the CD8＋ Treg cells induced in vitro by coculture with SK-OV-3/A2780 showed increased CTLA-4 and Foxp3 expression and decreased CD28 expression. In addition, the in vitro-induced CD8＋ Treg cells inhibited naive CD4＋ T-cell proliferation, which was partially mediated through TGF-β1 and IFN-γ. Our study suggests that CD8＋ Treg cells were increased in OC patients and could be induced in vitro, which may be the way that tumors limit antitumor immunity and evade immune surveillance.

关键词： CD8+ T cell ovarian cancer regulatory T cell tumor-infiltrating lymphocyte

A biomarker study in Peruvian males with breast cancer

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World Journal of Clinical Oncology 2021年第10期12卷 926-934页

作者： Carlos A Castaneda Miluska Castillo Luis A Bernabe Joselyn Sanchez Ebert Torres Nancy Suarez Katherine Tello Hugo Fuentes Jorge Dunstan Miguel De La Cruz Jose Manuel Cotrina Julio Abugattas Henry Guerra Henry L Gomez Faculty of Health Sciences Universidad Cientifica del SurLima 15067Peru Department of Medical Oncology Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Research Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Pathology Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Breast Cancer Surgery Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru

BACKGROUND Breast cancer(BC)frequency in males is extremely low and tumor features vary from its female *** cancer clinical and pathological features differ by race in *** infiltrating lymphocyte(TIL)levels,mismatch repair(MMR)protein loss,androgen receptor(AR)expression,and PIK3CA gene mutations are predictive biomarkers of response to biological therapy in female *** is limited information about clinical and pathological features as well as predictive biomarkers in males of non-Caucasian races with *** To investigate clinicopathological features and biomarkers of BC tumors in males and their prognostic value in Peruvian *** This study looked at a single-institution series of 54 Peruvian males with invasive BC who were diagnosed from Jan 2004 to June *** pathological features,TIL levels,MMR proteins,AR immunohistochemistry staining,and PIK3CA gene mutations were prospectively evaluated in cases with available paraffin *** of AR and estrogen receptor(ER)positive cells was additionally calculated by software after slide *** analyses included association tests,intraclass correlation test and Kaplan Meier overall survival *** The median age was 63 years and most cases were ER-positive(85.7%),HER2 negative(87.2%),Luminal-A phenotype(60%)and clinical stage II(41.5%)among our male breast *** TIL was 10%and higher levels tended to be associated with Luminal-B phenotype and higher ***-positive was found in 85.3%and was correlated with ER(intraclass index of 0.835,P<0.001).Loss of MMR proteins was found in 15.4%and PIK3CA mutation(H1047R)in 14.3%(belonged to the Luminal-A phenotype).Loss of MMR proteins was associated with AR-negative(P=0.018)but not with ER(P=0.43)or TIL(P=0.84).Early stages(P<0.001)and lower grade(P=0.006)were associated with longer overall *** status,phenotype,AR status,TIL level,MMR protein loss nor PIK3CA mutation was not associated

关键词： Male breast neoplasm Androgen receptor tumor-infiltrating lymphocyte Mismatch repair protein PIK3CA mutation