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Nucleic Acids Research Jul 2020Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the...
Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor-immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor-immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.
Topics: Algorithms; Gene Expression Profiling; Lymphocytes, Tumor-Infiltrating; Neoplasms; Software; Tumor Microenvironment
PubMed: 32442275
DOI: 10.1093/nar/gkaa407 -
BMC Medicine Jun 2021Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in... (Review)
Review
Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.
Topics: Humans; Immunotherapy, Adoptive; Lymphocytes; Lymphocytes, Tumor-Infiltrating; Neoplasms
PubMed: 34112147
DOI: 10.1186/s12916-021-02006-4 -
Journal For Immunotherapy of Cancer 2016Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer.... (Review)
Review
Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2 breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit. For HER2 breast cancers, type 1 T-cells, either increased TBET tumor infiltration or increased type 1 HER2-specific CD4 T-cells in the peripheral blood, are associated with better outcomes. Hormone receptor positive HER2 negative tumors tend to have the least immune infiltrate yet are the only breast cancer subtype to show worse prognosis with increased FOXP3 regulatory T-cell infiltrate. Notably, all breast cancer subtypes have tumors with low, intermediate, or high TIL infiltrate. Tumors with high TILs may also have increased PD-L1 expression which might be the reason that TN breast cancer seems to demonstrate the most robust clinical response to immune checkpoint inhibitor therapy but further investigation is needed. Tumors with intermediate or low levels of pre-treatment immune infiltrate, on the other hand, may benefit from an intervention that may increase TIL, particularly type 1 T-cells. Examples of these interventions include specific types of cytotoxic chemotherapy, radiation, or vaccine therapy. Therefore, the systematic evaluation of TIL and specific populations of TIL may be able to both guide prognosis and the appropriate sequencing of therapies in breast cancer.
Topics: Animals; Antigens, Surface; Antineoplastic Agents, Immunological; Biomarkers; Breast Neoplasms; Cytotoxicity, Immunologic; Female; Humans; Immunomodulation; Lymphocyte Count; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Molecular Targeted Therapy; Prognosis; Survival Analysis; Treatment Outcome
PubMed: 27777769
DOI: 10.1186/s40425-016-0165-6 -
Nature Dec 2019Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy. However, the reason some tumours...
Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.
Topics: Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Cell Differentiation; Disease Progression; Epigenesis, Genetic; Hepatocyte Nuclear Factor 1-alpha; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasms; Stem Cell Niche; Stem Cells; Transcription, Genetic; Tumor Escape
PubMed: 31827286
DOI: 10.1038/s41586-019-1836-5 -
Cells Jan 2021In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this... (Review)
Review
In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC prognosis and response to treatment. Indeed, the evaluation of TILs on primary tumors proved to be strongly prognostic in triple-negative (TN) BC patients treated with either adjuvant or neoadjuvant chemotherapy, as well as in early TNBC patients not receiving any systemic treatment, thus gaining level-1b evidence in this setting. In addition, a strong relationship between TILs and pathologic complete response after neoadjuvant chemotherapy has been reported in all BC subtypes and the prognostic role of higher TILs in early HER2-positive breast cancer patients has also been demonstrated. The interest in BC immune infiltrates has been further fueled by the introduction of the first immune checkpoint inhibitors in the treatment armamentarium of advanced TNBC in patients with PD-L1-positive status by FDA-approved assays. However, despite these advances, a biomarker capable of reliably and exhaustively predicting immunotherapy benefit in BC is still lacking, highlighting the imperative need to further deepen this issue. Finally, more comprehensive evaluation of immune infiltrates integrating both the quantity and quality of tumor-infiltrating immune cells and incorporation of TILs in composite scores encompassing other clinically or biologically relevant biomarkers, as well as the adoption of software-based and/or machine learning platforms for a more comprehensive characterization of BC immune infiltrates, are emerging as promising strategies potentially capable of optimizing patient selection and stratification in the research field. In the present review, we summarize available evidence and recent updates on immune infiltrates in BC, focusing on current clinical applications, potential clinical implications and major unresolved issues.
Topics: Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Immunity; Lymphocytes; Lymphoid Tissue; Tumor Microenvironment
PubMed: 33498711
DOI: 10.3390/cells10020223 -
Genome Biology Aug 2016Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new...
BACKGROUND
Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor-immune interactions in cancers.
RESULTS
We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at http://cistrome.org/TIMER .
CONCLUSIONS
We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may inform effective cancer vaccine and checkpoint blockade therapies.
Topics: Biomarkers, Tumor; Databases, Genetic; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Immune System; Immunity; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Models, Biological; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 27549193
DOI: 10.1186/s13059-016-1028-7 -
Frontiers in Immunology 2019Layilin (LAYN) is a critical gene that regulates T cell function. However, the correlations of LAYN to prognosis and tumor-infiltrating lymphocytes in different cancers...
Layilin (LAYN) is a critical gene that regulates T cell function. However, the correlations of LAYN to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. LAYN expression was analyzed via the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We evaluated the influence of LAYN on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between LAYN and cancer immune infiltrates was investigated via TIMER. In addition, correlations between LAYN expression and gene marker sets of immune infiltrates were analyzed by TIMER and GEPIA. A cohort (GSE17536) of colorectal cancer patients showed that high LAYN expression was associated with poorer overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). In addition, high LAYN expression was significantly correlated with poor OS and progression-free survival (PFS) in gastric cancers (OS HR = 1.97, = 3.6e-10; PFS HR = 2.12, = 2.3e-10). Moreover, LAYN significantly impacts the prognosis of diverse cancers via The Cancer Genome Atlas (TCGA). Specifically, high LAYN expression was correlated with worse OS and PFS in stage 2 to 4 but not stage 1 and stage N0 gastric cancer patients ( = 0.28, 0.34; = 0.073, 0.092). LAYN expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in colon adenocarcinoma (COAD) and stomach adenocarcinoma (STAD). LAYN expression showed strong correlations with diverse immune marker sets in COAD and STAD. These findings suggest that LAYN is correlated with prognosis and immune infiltrating levels of, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in colon and gastric cancer patients. In addition, LAYN expression potentially contributes to regulation of tumor-associated macrophages (TAMs), DCs, T cell exhaustion and Tregs in colon and gastric cancer. These findings suggest that LAYN can be used as a prognostic biomarker for determining prognosis and immune infiltration in gastric and colon cancers.
Topics: Biomarkers, Tumor; Colonic Neoplasms; Databases, Factual; Dendritic Cells; Female; Gene Expression Profiling; Humans; Kaplan-Meier Estimate; Lectins, C-Type; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Macrophages; Male; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Survival Analysis; Tumor Microenvironment
PubMed: 30761122
DOI: 10.3389/fimmu.2019.00006 -
Frontiers in Molecular Biosciences 2022Ferroptosis induced by SLC7A11 has an important translational value in the treatment of cancers. However, the mechanism of SLC7A11 in the pathogenesis of colon...
Ferroptosis induced by SLC7A11 has an important translational value in the treatment of cancers. However, the mechanism of SLC7A11 in the pathogenesis of colon adenocarcinoma (COAD) is rarely studied in detail. SLC7A11 expression was explored with The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) databases, and Western blot assay. The correlation of SLC7A11 expression with the abundance of infiltrating immune cells was evaluated the TIMER database. The relation of SLC7A11 expression with immune cell markers was investigated Gene Expression Profiling Interactive Analysis (GEPIA). The co-expression genes of SLC7A11 were screened by R packages, and the PPI was constructed the STRING database. SLC7A11 and co-expressed gene modulators were selected by NetworkAnalyst and DSigDB database. The correlations between SLC7A11 and cancer immune characteristics were analyzed the TIMER and TISIDB databases. SLC7A11 is overexpressed in most tumors, including COAD. The expression level of SLC7A11 has a significant correlation with the infiltration levels of CD8 T cells, neutrophils, and dendritic cells in COAD. The infiltrated lymphocyte markers of Th1 cell such as TBX21, IL12RB2, IL27RA, STAT1, and IFN-γ were strongly correlated with SLC7A11 expression. Five hub genes co-expressed with SLC7A11 that induce ferroptosis were identified, and mir-335-5p, RELA, and securinine have regulatory effects on it. SLC7A11 was negatively correlated with the expression of chemokines and chemokine receptors, such as CCL17, CCL19, CCL22, CCL23, CXCL14, CCR10, CX3CR1, and CXCR3, in COAD. SLC7A11 may play a role in induced ferroptosis and regulating tumor immunity, which can be considered as potential therapeutic targets in COAD.
PubMed: 35517862
DOI: 10.3389/fmolb.2022.889688 -
The Journal of Clinical Investigation Jul 2013CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce...
CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4⁺ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4⁺ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4⁺ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.
Topics: Antigens, CD; Breast Neoplasms; Case-Control Studies; Cytokines; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Oligonucleotide Array Sequence Analysis; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 23778140
DOI: 10.1172/JCI67428 -
Medicine Dec 2021Hepatocellular carcinoma (HCC) is a severe type of primary liver cancer with high postoperative recurrence. The prognosis predictability of tumor-infiltrating leukocytes...
Hepatocellular carcinoma (HCC) is a severe type of primary liver cancer with high postoperative recurrence. The prognosis predictability of tumor-infiltrating leukocytes (TILs) for patients who underwent HCC resection has been widely reported. However, limited information is available about TIL trafficking, which is also crucial for HCC patients.We included tumor tissue samples and clinical data from 89 HCC patients in this study and performed immunohistochemistry for CD3, CD8, FoxP3, and CD31. TILs were measured using an algorithm for quantification of tumor immune stroma (QTiS). Intratumoral microvessels were counted using Weidner's method. We first examined correlations among them and analyzed their relationships with clinical and survival data.Intratumoral microvessel density (iMVD) was significantly correlated with infiltration of CD3+ (r = 0.338, P = .001) and CD8+ (r = 0.320, P = .002) cells, but not FoxP3+ (r = 0.153, P = .152) cells. After multivariate analysis, higher infiltration of CD3+ (P = .038) independently showed significant predictability on better overall survival after resection of HCC. Although no influence of CD3+ (P = .386) and CD8+ (P = .648) cells were found on general disease-free survival, infiltration of CD3+ (P = .012), tumor size (P = .032) and albumin (P = .007) cells independently predicted late-phase disease-free survival. No significant relationships regarding iMVD, and infiltration of FoxP3+ cells with overall and disease-free survival were found.Our data suggest that increased iMVD could enrich tumor-infiltrating CD3+ cells. Infiltrated CD3+ cells could help to better predict both the overall and late-phase disease-free survival after resection of HCC.
Topics: Adolescent; Adult; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Forkhead Transcription Factors; Humans; Leukocytes; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Microvascular Density; Middle Aged; Young Adult
PubMed: 35049245
DOI: 10.1097/MD.0000000000028135