Dynamics of T-cell infiltration during the course of ovarian cancer: The gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells

2012 ◽  
Vol 132 (5) ◽  
pp. 1070-1079 ◽  
Author(s):  
Anna Fialová ◽  
Simona Partlová ◽  
Luděk Sojka ◽  
Hana Hromádková ◽  
Tomáš Brtnický ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Response ◽  
Effector Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Gradual Shift

scholarly journals Characterizing the tumor microenvironment of metastatic ovarian cancer by single cell transcriptomics

2020 ◽  
Author(s):  
Susan Olalekan ◽  
Bingqing Xie ◽  
Rebecca Back ◽  
Heather Eckart ◽  
Anindita Basu
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Population ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Transcriptional State ◽  
Target Cancer

AbstractEpithelial ovarian cancer is a highly heterogenous, metastatic and lethal disease. The presence of CD8+T cells within ovarian tumors is positively associated with overall patient survival. Determining if a patient has T cells that respond to immunotherapies, their characteristics and how they can be manipulated to target cancer cells is an area of intense investigation in cancer therapy. This study determines the cellular composition and the transcriptional state of immune cells in metastatic ovarian cancer samples from patients using single cell RNA sequencing (scRNA-seq). Hierarchical clustering stratified our patient cohort into 2 main groups: 1) a high T cell infiltration (high Tinf) group and 2) a low T cell infiltration (low Tinf) group. To assess the immune response in these patient samples, we performed an unsupervised clustering of the T cell population in each group. The T cell population clustered into 4 and 3 subpopulations in the high Tinf T cell and low Tinf respectively. A granulysin expressing T cell cluster was identified and unique to the High Tinf group. Interestingly, although both groups had resident memory CD8+T (CD8+Trm) cells, only the CD8+Trm cells in the high Tinf group expressed TOX, a recently described transcription factor. TOX confers longevity to T cells within immunosuppressive environment such as cancer. Interestingly, along with TOX+ T cells, we found a unique plasmablast cluster and an IRF8+ macrophage cluster unique to the high Tinf group. Our comprehensive scRNA-seq study provides important insights in elucidating the immune response in ovarian cancer patients.

scholarly journals Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy

2021 ◽  
Vol 9 (9) ◽  
pp. e003218
Author(s):  
James McAuliffe ◽  
Hok Fung Chan ◽  
Laurine Noblecourt ◽  
Ramiro Andrei Ramirez-Valdez ◽  
Vinnycius Pereira-Almeida ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Models ◽  
Murine Tumor ◽  
T Cell Infiltration

BackgroundThe clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy.MethodsHere, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses.ResultsThe ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells.ConclusionsThese findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.

scholarly journals 49 In situ phenotypic analysis of T cells in the tumor microenvironment of a pre-clinical model of non-small cell lung cancer (NSCLC) by tissue sectioning and whole-mount immunofluorescence imaging

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A52-A52
Author(s):  
Elen Torres ◽  
Stefani Spranger
Keyword(s):  
T Cells ◽  
Spatial Distribution ◽  
T Cell ◽  
Spatial Location ◽  
Cell Infiltration ◽  
Cell Populations ◽  
Tumor Bearing ◽  
T Cell Infiltration ◽  
Volume Imaging ◽  
Whole Mount

BackgroundUnderstanding the interactions between tumor and immune cells is critical for improving current immunotherapies. Pre-clinical and clinical evidence has shown that failed T cell infiltration into lung cancer lesions might be associated with low responsiveness towards checkpoint blockade.1 For this reason, it is necessary to characterize not only the phenotype of T cells in tumor-bearing lungs but also their spatial location in the tumor microenvironment (TME). Multiplex immunofluorescence staining allows the simultaneous use of several cell markers to study the state and the spatial location of cell populations in the tissue of interest. Although this technique is usually applied to thin tissue sections (5 to 12 µm), the analysis of large tissue volumes may provide a better understanding of the spatial distribution of cells in relation to the TME. Here, we analyzed the number and spatial distribution of cytotoxic T cells and other immune cells in the TME of tumor-bearing lungs, using both 12 µm sections and whole-mount preparations imaged by confocal microscopy.MethodsLung tumors were induced in C57BL/6 mice by tail vein injection of a cancer cell line derived from KrasG12D/+ and Tp53-/- mice. Lung tissue with a diverse degree of T cell infiltration was collected after 21 days post tumor induction. Tissue was fixed in 4% PFA, followed by snap-frozen for sectioning. Whole-mount preparations were processed according to Weizhe Li et al. (2019) 2 for tissue clearing and multiplex volume imaging. T cells were labeled with CD8 and FOXP3 antibodies to identify cytotoxic or regulatory T cells, respectively. Tumor cells were labeled with a pan-Keratin antibody. Images were acquired using a Leica SP8 confocal microscope. FIJI3 and IMARIS were used for image processing.ResultsWe identified both cytotoxic and regulatory T cell populations in the TME using thin sections and whole-mount. However, using whole-mount after tissue clearing allowed us to better evaluate the spatial distribution of the T cell populations in relation to the tumor structure. Furthermore, tissue clearance facilitates the imaging of larger volumes using multiplex immunofluorescence.ConclusionsAnalysis of large lung tissue volumes provides a better understanding of the location of immune cell populations in relation to the TME and allows to study heterogeneous immune infiltration on a per-lesion base. This valuable information will improve the characterization of the TME and the definition of cancer-immune phenotypes in NSCLC.ReferencesTeng MW, et al., Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015;75(11): p. 2139–45.Li W, Germain RN, and Gerner MY. High-dimensional cell-level analysis of tissues with Ce3D multiplex volume imaging. Nat Protoc 2019;14(6): p. 1708–1733.Schindelin J, et al, Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9(7): p. 676–82.

scholarly journals Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy

2021 ◽  
Vol 9 (10) ◽  
pp. e003671
Author(s):  
Kim E Kortekaas ◽  
Saskia J Santegoets ◽  
Liselotte Tas ◽  
Ilina Ehsan ◽  
Pornpimol Charoentong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Squamous Cell ◽  
Molecular Subtype ◽  
Cell Infiltration ◽  
Immune Signaling ◽  
T Cell Infiltration ◽  
Expression Of Genes

BackgroundA profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.MethodsThe type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I–III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.ResultsHigh intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γ signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ~60% of the altered-excluded VSCC.ConclusionAn active immune signaling profile is present in 35% of primary FIGO I–III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.

scholarly journals Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states

2020 ◽  
Author(s):  
Victor Tkachev ◽  
James Kaminski ◽  
E. Lake Potter ◽  
Scott N. Furlan ◽  
Alison Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cell ◽  
Transcriptomic Analysis ◽  
Cell Infiltration ◽  
Cell Transplant ◽  
Gi Tract ◽  
Tissue Invasion ◽  
T Cell Infiltration

ABSTRACTOne of the central challenges in the field of allo-immunity is deciphering the mechanisms driving T cells to infiltrate and subsequently occupy target organs to cause disease. The act of CD8-dominated T cell infiltration is critical to acute graft-versus-host disease (aGVHD), wherein donor T cells become activated, tissue-infiltrating and highly cytotoxic, causing wide-spread tissue damage after allogeneic hematopoietic stem cell transplant (allo-HCT). However, in human and non-human primate studies, deconvolving the transcriptional programs of newly recruited relative to resident memory T cells in the gastrointestinal (GI) tract has remained a challenge. In this study, we combined the novel technique of Serial Intravascular Staining (SIVS) with single-cell RNA-Seq (scRNA-seq) to enable detailed dissection of the tightly connected processes by which T cells first infiltrate tissues and then establish a pathogenic tissue residency program after allo-HCT in non-human primates. Our results have enabled the creation of a spatiotemporal map of the transcriptional drivers of CD8 T cell infiltration into the primary aGVHD target-organ, the GI tract. We identify the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphdepletion-driven T cell infiltration. The donor CD8 T cells that infiltrate the GI tract demonstrate a highly activated, cytotoxic phenotype while simultaneously rapidly developing canonical tissue-resident memory (TRM) protein expression and transcriptional signatures, driven by IL-15/IL-21 signaling. Moreover, by combining SIVS and transcriptomic analysis, we have been able to work backwards from this pathogenic TRM programing, and, for the first time, identify a cluster of genes directly associated with tissue invasiveness, prominently including specific chemokines and adhesion molecules and their receptors, as well as a central cytoskeletal transcriptional node. The clinical relevance of this new tissue invasion signature was validated by its ability to discriminate the CD8 T cell transcriptome of patients with GI aGVHD. These results provide new insights into the mechanisms controlling tissue infiltration and pathogenic CD8 TRM transcriptional programing, uncovering critical transitions in allo-immune tissue invasion and destruction.One sentence summaryFlow cytometric and transcriptomic analysis reveals coordinated tissue-infiltration and tissue-residency programs driving gastrointestinal aGVHD.

Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1370-1377 ◽  
Author(s):  
Shin-ichiro Kagami ◽  
Hiroshi Nakajima ◽  
Kotaro Kumano ◽  
Kotaro Suzuki ◽  
Akira Suto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Specific Ige ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Cell Recruitment ◽  
Eosinophil Recruitment ◽  
Airway Eosinophilia ◽  
T Cell Infiltration

Antigen-induced eosinophil recruitment into the airways of sensitized mice is mediated by CD4+ T cells and their cytokines, especially IL-5. In this study, we found that the antigen-induced airway eosinophilia was diminished in Stat5a-deficient (Stat5a−/−) mice and Stat5b-deficient (Stat5b−/−) mice. We also found that antigen-induced CD4+ T-cell infiltration and IL-5 production in the airways were diminished in Stat5a−/− mice and Stat5b−/− mice. Moreover, antigen-induced proliferation of splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice, suggesting that the generation of antigen-primed T cells may be compromised in Stat5a−/−mice and Stat5b−/− mice and this defect may account for the diminished antigen-induced T-cell infiltration into the airways. Interestingly, IL-4 and IL-5 production from anti-CD3–stimulated splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice. However, antigen-specific IgE and IgG1 production was diminished in Stat5a−/− mice but not in Stat5b−/− mice, whereas antigen-specific IgG2a production was increased in Stat5a−/− mice, suggesting the enhanced Th1 responses in Stat5a−/− mice. Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a−/− mice and Stat5b−/− mice. Together, these results indicate that both Stat5a and Stat5b are essential for induction of antigen-induced eosinophil recruitment into the airways and that the defects in antigen-induced eosinophil recruitment in Stat5a−/− mice and Stat5b−/− mice result from both impaired IL-5 production in the airways and diminished IL-5 responsiveness of eosinophils.

scholarly journals Adoptive cellular therapy enhances the helper T cell response and reduces the number of regulatory T cells

2011 ◽  
Vol 2 (4) ◽  
pp. 737-743 ◽  
Author(s):  
TAKESHI ISHIKAWA ◽  
SATOSHI KOKURA ◽  
NAOYUKI SAKAMOTO ◽  
TSUGUHIRO MATSUMOTO ◽  
JUN FUNAKI ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Response ◽  
Cellular Therapy ◽  
T Cell Response ◽  
Helper T Cell ◽  
Adoptive Cellular Therapy
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