Nuclear Respiratory Factor 1 Associated with Prognosis and Immune Infiltration in Hepatocellular Carcinoma

Abstract Background: Recent studies have shown that functional mitochondria are essential for cancer cells. Nuclear respiratory factor 1 (NRF1) is a transcription factor that activates mitochondrial biogenesis and the expression of the respiratory chain, but little is known about its prognostic value and tumor-infiltrating lymphocytes association. Here, we evaluated the association among expression of NRF1, clinicopathological characteristics, survival and immune infiltration in hepatocellular carcinoma (HCC).Methods: We used the Tumor Immune Estimation Resource (TIMER) to analyze the difference of NRF1 mRNA expression in human cancers. Clinical-pathological information and follow-up data were collected from HCC (n = 171) and chronic hepatitis (n = 113) patients. NRF1 expression were scored based on the percentage and intensity of immunohistochemical staining in pathological slides. Correlations between clinical features and the expression of NRF1 were evaluated by Chi-square test, Kaplan-Meier curves, logrank tests and multivariate Cox regression analysis. The correlations between NRF1 expression and gene marker sets of tumor infiltrating lymphocytes (TILs) were analyzed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Results: NRF1 mRNA expression was significantly higher in HCC than in normal tissue. Compared with chronic hepatitis, more frequency of NRF1 high expression are found in HCC (31.58 % vs 13.27 %, P < 0.001, P < 0.001). In addition, the NRF1 expression was significantly associated with hepatic cirrhosis (P = 0.021) and vascular invasion (P = 0.025). NRF1 expression was also a significant independent predictor of survival in HCC (P = 0.003; HRadj = 0.20; 95% CI = 0.09 – 0.44). NRF1 showed positively correlated with TILs, including B cell (r = 0.384, P = 1.68e-13), CD8+ T cells (r = 0.246, P = 3.99e-06), CD4+ T cells (r = 0.535, P = 6.90e-27), macrophage (r = 0.506, P = 1.52e-23), neutrophils (r = 0.465, P = 6.08e-20) and dendritic cell (r = 0.404, P = 8.61e-15). The marker genes of TILs correlated significantly with NRF1 expression.Conclusions: NRF1 expression was a useful independent prognostic factor and correlated with tumor immune infiltration in HCC.

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High levels of tumor-infiltrating lymphocytes showed better clinical outcomes in FOLFOX-treated gastric cancer patients

Pharmacogenomics ◽

10.2217/pgs-2019-0102 ◽

2020 ◽

Vol 21 (11) ◽

pp. 751-759

Author(s):

Wei Li ◽

Weili Wang ◽

Ping Liao ◽

Kun Song ◽

Zhanwei Zhu ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Clinical Outcomes ◽

Cox Regression ◽

Tumor Infiltrating Lymphocytes ◽

Median Number ◽

Cox Regression Analysis ◽

T Cell Infiltration ◽

Gastric Cancer Patients ◽

Infiltrating Lymphocytes

Background: Tumor-infiltrating lymphocytes (TILs) and postoperative chemotherapeutics interact in the tumor micro-environment. This interaction has not been well investigated in gastric cancer. Materials & methods: A total of 129 patients were divided into high or low TILs based on the median number of positive CD3+ and FoxP3+ T cells, which was assessed by immunocytochemistry. Results: Cox regression analysis showed that the stage III disease with shorter overall survival was significant. The analysis showed that high numbers of CD3+ or FoxP3+ T cells have better clinical outcomes in FOLFOX-treated patients. Conclusion: High CD3+ and FoxP3+ T-cell infiltration was associated with better clinical outcomes in patients with gastric cancer treated with FOLFOX, suggesting TILs incorporated into algorithms to improve the therapeutic efficacy of optimal chemotherapy.

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Increased mRNA expression of chemokines in hepatocellular carcinoma with tumor-infiltrating lymphocytes

Journal of Gastroenterology and Hepatology ◽

10.1111/j.1440-1746.2006.04551.x ◽

2006 ◽

Vol 0 (0) ◽

pp. 060726060227001-??? ◽

Cited By ~ 3

Author(s):

Seitaro Hirano ◽

Yukio Iwashita ◽

Atsushi Sasaki ◽

Seiichiro Kai ◽

Masayuki Ohta ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Mrna Expression ◽

Tumor Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

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Prognostic Impact of APOBEC3B Expression in Metastatic Urothelial Carcinoma and Its Association with Tumor-Infiltrating Cytotoxic T Cells

Current Oncology ◽

10.3390/curroncol28030154 ◽

2021 ◽

Vol 28 (3) ◽

pp. 1652-1662

Author(s):

Hyunho Kim ◽

Okran Kim ◽

Myung Ah Lee ◽

Ji Youl Lee ◽

Sung-Hoo Hong ◽

...

Keyword(s):

T Cells ◽

Confidence Interval ◽

Urothelial Carcinoma ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Platinum Based Chemotherapy ◽

Metastatic Urothelial Carcinoma ◽

Infiltrating Lymphocytes

APOBEC3B enzymes are endogenous carcinogenic mutagens. Metastatic urothelial carcinomas often harbor APOBEC3B-mediated mutations in which tCw to T or G substitution occurs. Here, we evaluated patient survival and CD8+ T-cell density according to APOBEC3B expression in patients with metastatic urothelial carcinoma who underwent cytotoxic chemotherapy. We performed a retrospective study on 94 patients with urothelial carcinoma who were treated with first line palliative chemotherapy. APOBEC3B expression and CD8+/CD3+ ratio of tumor-infiltrating lymphocytes were evaluated using immunohistochemistry. Kaplan–Meier survival curves were generated and the log-rank test was employed. The association between APOBEC3B expression and tumor-infiltrating lymphocytes was analyzed using Pearson’s chi-squared test. High APOBEC3B expression was detected in 71 of the 94 patients (75.5%). The median overall survival was longer in patients with high APOBEC3B expression (15 months) than in those with low expression (p = 0.045). The hazard ratio obtained based on the Cox regression analysis was 0.292 (95% confidence interval 0.118–0.723, p = 0.008). APOBEC3B expression was associated with the CD8+/CD3+ ratio (2.914, 95% confidence interval 1.030–8.249, p = 0.039). Collectively, APOBEC3B expression was an independent prognostic factor in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. Tumor-infiltrating cytotoxic T cells were associated with APOBEC3B expression.

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TREM2 is a prognostic biomarker and correlates in immune infiltrates in kidney renal papillary cell carcinoma and liver hepatocellular carcinoma

10.21203/rs.3.rs-170595/v1 ◽

2021 ◽

Author(s):

bin wen Xiang ◽

Sha Fang ◽

peng yan Ding ◽

min nuo Liu ◽

chao hua Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Carcinoma ◽

Tumor Infiltrating Lymphocytes ◽

Mrna Levels ◽

Limited Information ◽

Immune Infiltration ◽

Kaplan Meier ◽

Positive Correlations ◽

Liver Hepatocellular Carcinoma ◽

Infiltrating Lymphocytes

Abstract Background: TREM2 was identified as a marker for tumor-associated macrophages (TAMs) and monocytes. However, there is limited information concerning the TREM2 mRNA levels correlated with the outcome and tumor-infiltrating lymphocytes in different cancers.Methods: To explore the expression pattern and prognostic value of TREM2 in pan-cancer, We use multiple databases, including ONCOMINE, PrognoScan, Kaplan-Meier Plotter, GEPIA, and TIMER. we investigated the correlations between TREM1 expression and immune infiltration in cancers, especially kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC)Results: According to the results from Oncomine and TIMER datasets, in a general way, TREM2 mRNA expression is higher in the majority of the tumor and is lower in lung cancer, compared with normal adjacent tissues. A high expression level of TREM2 was beneficial to the survival of LIHC patients. Both in KIRP and LIHC, TREM2 expression levels showed significant positive correlations with infiltrating levels of macrophages and dendritic cells. It also correlated with diverse immune marker sets. We can also find that TREM2 expression was modestly associated with CD8+T cells in KIRP. However, it is related to the Treg in LIHC.Conclusions: TREM2 may be a prognostic marker in the multitudinous tumor. Furthermore, TREM2 may interact with immune infiltration to influence patient survival in cancers like LIHC and KIRP.

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Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.4565 ◽

2007 ◽

Vol 25 (18) ◽

pp. 2586-2593 ◽

Cited By ~ 683

Author(s):

Qiang Gao ◽

Shuang-Jian Qiu ◽

Jia Fan ◽

Jian Zhou ◽

Xiao-Ying Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Cox Regression ◽

Independent Predictor ◽

Cytotoxic T Cells ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Tissue Microarrays ◽

Kaplan Meier ◽

Infiltrating Lymphocytes

Purpose To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. Patients and Methods CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. Results CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Conclusion Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.

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773 Adoptive Cell Therapy Response in Melanoma is Mediated by Stem-like CD8 T cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0773 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A822-A822

Author(s):

Sri Krishna ◽

Frank Lowery ◽

Amy Copeland ◽

Stephanie Goff ◽

Grégoire Altan-Bonnet ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Single Cell ◽

Cd8 T Cells ◽

Tumor Infiltrating Lymphocytes ◽

High Dimensional ◽

Tumor Control ◽

Intrinsic Factors ◽

Infiltrating Lymphocytes

BackgroundAdoptive T cell therapy (ACT) utilizing ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) can result in complete regression of human cancers.1 Successful immunotherapy is influenced by several tumor-intrinsic factors.2 3 Recently, T cell-intrinsic factors have been associated with immunotherapy response in murine and human studies.4 5 Analyses of tumor-reactive TILs have concluded that anti-tumor neoantigen-specific TILs are enriched in subsets defined by the expression of PD-1 or CD39.6 7 Thus, there is a lack of consensus regarding the tumor-reactive TIL subset that is directly responsible for successful immunotherapies such as ICB and ACT. In this study, we attempted to define the fitness landscape of TIL-enriched infusion products to specifically understand its phenotypic impact on human immunotherapy responses.MethodsWe compared the phenotypic differences that could distinguish bulk ACT infusion products (I.P.) administered to patients who had complete response to therapy (complete responders, CRs, N = 24) from those whose disease progressed following ACT (non-responders, NRs, N = 30) by high dimensional single cell protein and RNA analysis of the I.P. We further analyzed the phenotypic states of anti-tumor neoantigen specific TILs from patient I.P (N = 26) by flow cytometry and single cell transcriptomics.ResultsWe identified two CD8+ TIL populations associated with clinical outcomes: a memory-progenitor CD39-negative stem-like TIL (CD39-CD69-) in the I.P. associated with complete cancer regression (overall survival, P < 0.0001, HR = 0.217, 95% CI 0.101 to 0.463) and TIL persistence, and a terminally differentiated CD39-positive TIL (CD39+CD69+) population associated with poor TIL persistence post-treatment. Although the majority (>65%) of neoantigen-reactive TILs in both responders and non-responders to ACT were found in the differentiated CD39+ state, CR infusion products also contained a pool of CD39- stem-like neoantigen-specific TILs (median = 8.8%) that was lacking in NR infusion products (median = 23.6%, P = 1.86 x 10-5). Tumor-reactive stem-like T cells were capable of self-renewal, expansion, and persistence, and mediated superior anti-tumor response in vivo.ConclusionsOur results support the hypothesis that responders to ACT received infusion products containing a pool of stem-like neoantigen-specific TILs that are able to undergo prolific expansion, give rise to differentiated subsets, and mediate long-term tumor control and T cell persistence, in line with recent murine ICB studies mediated by TCF+ progenitor T cells.4 5 Our data also suggest that TIL subsets mediating ACT-response (stem-like CD39-) might be distinct from TIL subsets enriched for anti-tumor-reactivity (terminally differentiated CD39+) in human TIL.6 7AcknowledgementsWe thank Don White for curating the melanoma patient cohort, and J. Panopoulos (Flowjo) for helpful discussions on high-dimensional analysis, and NCI Surgery Branch members for helpful insights and suggestions. S. Krishna acknowledges funding support from NCI Director’s Innovation Award from the National Cancer Institute.Trial RegistrationNAEthics ApprovalThe study was approved by NCI’s IRB ethics board.ReferencesGoff SL, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–2397.Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019;176:404.Miller BC, et al. Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol 2019;20:326–336.Simoni Y, et al. Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575–579.Gros A, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014;124:2246–2259.

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Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

Clinical & Translational Oncology ◽

10.1007/s12094-021-02652-3 ◽

2021 ◽

Author(s):

H. Kuroda ◽

T. Jamiyan ◽

R. Yamaguchi ◽

A. Kakumoto ◽

A. Abe ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Associated Macrophages ◽

Free Survival ◽

Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells

International Journal of Cancer ◽

10.1002/ijc.21894 ◽

2006 ◽

Vol 119 (4) ◽

pp. 831-838 ◽

Cited By ~ 25

Author(s):

Sine Reker Hadrup ◽

Otto Brændstrup ◽

Grete Krag Jacobsen ◽

Svend Mortensen ◽

Lars Østergaard Pedersen ◽

...

Keyword(s):

T Cells ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

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Promoter Methylation ofSFRP3Is Frequent in Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2014/351863 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Ya-Wen Lin ◽

Yu-Lueng Shih ◽

Gi-Shih Lien ◽

Fat-Moon Suk ◽

Chung-Bao Hsieh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Mrna Expression ◽

Cell Lines ◽

Promoter Methylation ◽

Promoter Hypermethylation ◽

Polymerase Chain ◽

Related Proteins ◽

And Control

Oncogenic activation of the Wnt/β-catenin signaling pathway is common in human cancers. The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in carcinogenesis. Because there have been no reports about the role ofSFRP3in hepatocellular carcinoma (HCC), we investigated the level of methylation and transcription ofSFRP3. Four HCC cell lines, 60 HCCs, 23 cirrhosis livers, 37 chronic hepatitis livers, and 30 control livers were prescreened forSFRP3promoter methylation by methylation-specific polymerase chain reaction (MS-PCR) and bisulfite sequencing.SFRP3promoter methylation was observed in 100%, 60%, 39.1%, 16.2%, and 0% in HCC cell lines, primary HCCs, cirrhosis livers, chronic hepatitis livers, and control livers, respectively. Demethylation treatment with 5-aza-2′-deoxycytidine in HCC cells restored or increased theSFRP3mRNA expression. We next used quantitative MS-PCR (QMSP) to analyze the methylation level ofSFRP3in 60 HCCs and their corresponding nontumor tissues. Methylation ofSFRP3promoter region in HCCs increased significantly compared with control tissues. There is a positive correlation between promoter hypermethylation andSFRP3mRNA downregulation. Our data suggest that promoter hypermethylation ofSFRP3is a common event in HCCs and plays an important role in regulation ofSFRP3mRNA expression.

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Identification of Immune-Related Prognostic mRNA and lncRNA in Patients with Hepatocellular Carcinoma

Journal of Oncology ◽

10.1155/2022/5313149 ◽

2022 ◽

Vol 2022 ◽

pp. 1-16

Author(s):

Dan Chen ◽

Xiaoting Li ◽

Hui Li ◽

Kai Wang ◽

Xianghua Tian

Keyword(s):

Hepatocellular Carcinoma ◽

Flow Cytometry ◽

T Cells ◽

Regression Analysis ◽

Survival Analysis ◽

Immune Cells ◽

Cox Regression ◽

Differentially Expressed ◽

Cox Regression Analysis ◽

Immune Related Genes

Background. As the most common hepatic malignancy, hepatocellular carcinoma (HCC) has a high incidence; therefore, in this paper, the immune-related genes were sought as biomarkers in liver cancer. Methods. In this study, a differential expression analysis of lncRNA and mRNA in The Cancer Genome Atlas (TCGA) dataset between the HCC group and the normal control group was performed. Enrichment analysis was used to screen immune-related differentially expressed genes. Cox regression analysis and survival analysis were used to determine prognostic genes of HCC, whose expression was detected by molecular experiments. Finally, important immune cells were identified by immune cell infiltration and detected by flow cytometry. Results. Compared with the normal group, 1613 differentially expressed mRNAs (DEmRs) and 1237 differentially expressed lncRNAs (DElncRs) were found in HCC. Among them, 143 immune-related DEmRs and 39 immune-related DElncRs were screened out. These genes were mainly related to MAPK cascade, PI3K-AKT signaling pathway, and TGF-beta. Through Cox regression analysis and survival analysis, MMP9, SPP1, HAGLR, LINC02202, and RP11-598F7.3 were finally determined as the potential diagnostic biomarkers for HCC. The gene expression was verified by RT-qPCR and western blot. In addition, CD4 + memory resting T cells and CD8 + T cells were identified as protective factors for overall survival of HCC, and they were found highly expressed in HCC through flow cytometry. Conclusion. The study explored the dysregulation mechanism and potential biomarkers of immune-related genes and further identified the influence of immune cells on the prognosis of HCC, providing a theoretical basis for the prognosis prediction and immunotherapy in HCC patients.

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