458 Antitumor mechanisms of local radiation and combination immunotherapy in an immunologically cold model of neuroblastoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A486-A486
Author(s):  
Taylor Aiken ◽  
Julie Voeller ◽  
Amy Erbe ◽  
Alexander Rakhmilevich ◽  
Paul Sondel
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mhc Class I ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
Cell Depletion ◽  
Class I ◽  
Combination Immunotherapy ◽  
T Cell Depletion

BackgroundThe standard treatment for high-risk neuroblastoma includes a combination immunotherapeutic approach consisting of IL-2, GM-CSF, and monoclonal antibodies directed against GD2, a disialoganglioside preferentially expressed in neuroblastoma and melanoma (1). We recently described an effective a preclinical in-situ vaccination strategy combining local radiation therapy (RT), IL-2-linked to anti-GD2 monoclonal antibody (intratumoral immunocytokine, IT-IC), checkpoint inhibition (anti-CTLA4), and drivers of innate immunity (anti-CD40 and CpG) (2). This strategy is effective in curing mice with immunologically-cold neuroblastoma. We sought to better characterize the anti-tumor mechanisms that mediate this effect.MethodsMice bearing GD2-expressing, immunologically-cold neuroblastoma tumors (9464D-GD2) were treated with 12Gy RT and combination immunotherapy (IT-IC, anti-CTLA-4, CpG, anti-CD40) over 12 days as previously described (2). Depletion of individual immune cell sets during treatment was achieved by depleting monoclonal antibodies and confirmed by flow cytometry. T-cell receptor deficient (TCR KO) mice were used to confirm findings in T-cell depletion experiments. 9464D-GD2 parental cells have low MHC-I expression; subclones with low and moderate MHC Class I expression were obtained by flow cytometry sorting and the impact of MHC class I expression on immune cell infiltrate and survival was assessed.ResultsThe effectiveness of RT and combination immunotherapy was not significantly reduced by NK or T cell depletion, and TCR KO mice had similar tumor growth and survival to mice that underwent T-cell depletion. Moderate MHC class I expression did not slow tumor growth or improve survival in mice bearing 9464D-GD2 tumors (over those with low MHC-I) following treatment. Moderate MHC class I expression also did not alter individual immune cell subsets in treated tumors. Overall, increased infiltration of CD8 T-cells, CD4 T-cells, and depletion of T regulatory cells was observed in all treated tumors (p<0.05).Abstract 458 Figure 1Effect of MHC class I expression on response to RT and combination immunotherapy (IT-IC, anti-CTLA4, anti-CD40, CpG). A) Increased MHC class I expression in 9464D-GD2 derived tumors did not alter tumor growth or survival following treatment. B) Increased MHC class I expression did not alter immune subsets following treatment of 9464D-GD tumors with radiation and combination immunotherapy. Increased numbers of CD8+ and CD4+ T-cells was observed with both moderate and absent MHC class I expression. T regulatory cells were also effectively depleted in both treated groupsConclusionsTreatment with RT and combination immunotherapy (IT-IC, anti-CTLA4, anti-CD40, CpG) may act through mechanisms that are MHC class I, NK-cell and T-cell independent. Further investigation of the role of innate immunity and myeloid subsets in this scenario is warranted.AcknowledgementsResearch reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32 CA090217.ReferencesYu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma. New England Journal of Medicine 2010;363:1324–34Voeller J, Erbe AK, Slowinski J, Rasmussen K, Carlson PM, Hoefges A, et al. Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. Journal for Immunotherapy of Cancer 2019;7:13

scholarly journals Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses

2020 ◽  
Vol 8 (2) ◽  
pp. e000605
Author(s):  
Souvik Dey ◽  
Erika Sutanto-Ward ◽  
Katharina L Kopp ◽  
James DuHadaway ◽  
Arpita Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mhc Class I ◽  
Adoptive Transfer ◽  
Immune Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Class I ◽  
Antitumor Effects

BackgroundThe tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.MethodsCT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting.ResultsThis study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread.ConclusionsThe in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.

scholarly journals Activation and Proliferation of PD-1+ Kidney Double-Negative T Cells Is Dependent on Nonclassical MHC Proteins and IL-2

2019 ◽  
Vol 30 (2) ◽  
pp. 277-292 ◽  
Author(s):  
Mohanraj Sadasivam ◽  
Sanjeev Noel ◽  
Sul A. Lee ◽  
Jing Gong ◽  
Mohamad E. Allaf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Knockout Mice ◽  
Immune Cell ◽  
Kidney Diseases ◽  
Sterile Inflammation ◽  
T Cell Subsets ◽  
Class I ◽  
Double Negative

BackgroundCD4− CD8− double-negative (DN) αβ T cells with innate-like properties represent a significant component of T cells in human and mouse kidneys. They spontaneously proliferate in the steady state and protect against ischemic AKI. However, the mechanisms regulating DN T cell homeostasis and responses to external danger signals from “sterile” inflammation remain poorly understood.MethodsWe used knockout mice, functional assays, and an established ischemic AKI model to investigate the role of various MHC class I and II molecules in regulating kidney DN T cells. We also studied human nephrectomy samples.ResultsDeficiency of β2m-dependent MHC class I (but not MHC class II) molecules led to significant reduction in frequency or absolute numbers of kidney DN T cells due to impaired activation, proliferation, increased apoptosis, and loss of an NK1.1+ subset of DN T cells. The remaining DN T cells in β2m knockout mice mainly comprised a programmed cell death protein-1 receptor (PD-1+) subset that depends on IL-2 provided by conventional T cells for optimal homeostasis. However, this PD-1+ subset remained highly responsive to changes in milieu, demonstrated by responses to infused lymphocytes. It was also the major responder to ischemic AKI; the NK1.1+ subset and CD8+ T cells had minimal responses. We found both DN T cell subsets in normal and cancerous human kidneys, indicating possible clinical relevance.ConclusionsDN T cells, a unique population of kidney T cells, depend on nonclassical β2m molecules for homeostasis and use MHC-independent mechanisms to respond to external stimuli. These results have important implications for understanding the role these cells play during AKI and other immune cell–mediated kidney diseases.

scholarly journals IMMU-48. CD4+ T CELLS RESTRICT MEDULLOBLASTOMA GROWTH AND DISSEMINATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii115-ii115
Author(s):  
Tanja Eisemann ◽  
Robert Wechsler-Reya
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Depletion ◽  
Immune Microenvironment ◽  
T Cell Depletion ◽  
Tumor Growth And Metastasis

Abstract The immune system serves as a powerful defense not only against pathogens and parasites but also against neoplastic cells. Emerging immunotherapies that boost the activity of tumor-reactive immune cells or counteract immune suppressive mechanisms have shown promising effects in certain types of cancer. However, the success of immunotherapy for brain tumors has been limited, highlighting the need for a better understanding of the immune microenvironment in these tumors. Our previous studies have shown that T cells critically affect growth of the pediatric brain tumor medulloblastoma. In particular, depletion of CD4+ T cells results in more aggressive growth of medulloblastoma cells and allows these cells to metastasize to the spinal cord. The anti-tumoral effects of CD4+ T cells are not due to their function as helpers for CD8+ cytotoxic T cells, since CD8+ T cell depletion did not enhance tumor growth to the same extent as CD4+ T cell depletion. To test whether CD4+ T cells can recognize MHC class II molecules on tumor cells and attack these cells directly, we generated tumors from MHC class II knockout mice. Surprisingly, depletion of CD4+ cells in these animals still enhanced tumor growth and metastasis. These results suggest that CD4+ T cells regulate medulloblastoma growth and metastasis in a manner that is independent of CD8+ T cells and independent of MHC-II on tumor cells. Ongoing studies are aimed at elucidating the mechanisms by which CD4+ T cells regulate medulloblastoma growth, including the antigen-presenting cells that activate them and the effector cells responsible for killing tumor cells following their activation. These studies will advance our understanding of the immune microenvironment in medulloblastoma and allow us to design more effective therapies for controlling tumor growth and metastasis.

T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4930-4936 ◽  
Author(s):  
Lotta Hansson ◽  
Hodjattallah Rabbani ◽  
Jan Fagerberg ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Heavy Chain ◽  
T Cell Response ◽  
Class I ◽  
Type I ◽  
T Cell Epitopes ◽  
Hla Binding

Abstract The idiotypic structure of the monoclonal immunoglobulin (Ig) in multiple myeloma (MM) might be regarded as a tumor-specific antigen. The present study was designed to identify T-cell epitopes of the variable region of the Ig heavy chain (VH) in MM (n = 5) using bioinformatics and analyze the presence of naturally occurring T cells against idiotype-derived peptides. A large number of human-leukocyte-antigen (HLA)–binding (class I and II) peptides were identified. The frequency of predicted epitopes depended on the database used: 245 in bioinformatics and molecular analysis section (BIMAS) and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low or intermediate affinity range. The majority of the predicted peptides were complementarity-determining region (CDR)–rather than framework region (FR)–derived (52%-60% vs 40%-48%, respectively). Most of the predicted peptides were confined to the CDR2-FR3-CDR3 “geographic” region of the Ig-VH region (70%), and significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (P &lt; .01). There were 8– to 10–amino acid (aa) long peptides corresponding to the CDRs and fitting to the actual HLA-A/B haplotypes that spontaneously recognized, albeit with a low magnitude, type I T cells (interferon γ), indicating an ongoing major histocompatibility complex (MHC) class I–restricted T-cell response. Most of those peptides had a low binding half-life (BIMAS) and a low/intermediate score (SYFPEITHI). Furthermore, 15- to 20-aa long CDR1-3–derived peptides also spontaneously recognized type I T cells, indicating the presence of MHC class II–restricted T cells as well. This study demonstrates that a large number of HLA-binding idiotypic peptides can be identified in patients with MM. Such peptides may spontaneously induce a type I MHC class I– as well as class II–restricted memory T-cell response.

scholarly journals Human bone marrow and peripheral blood T lymphocyte depletion: efficacy and effects of both T cells and monocytes on growth of hematopoietic progenitors

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 663-679
Author(s):  
L Levitt ◽  
TJ Kipps ◽  
EG Engleman ◽  
PL Greenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Cell Depletion ◽  
Target Cells ◽  
Facs Analysis ◽  
Hematopoietic Progenitors ◽  
T Cell Depletion

The efficacy of four separate methods of human bone marrow T lymphocyte depletion was assessed, and the effect of T cells and monocytes on in vitro growth of marrow (CFU-GEMM, BFU-E, and CFU-GM) and peripheral blood (BFU-E) hematopoietic progenitors was determined. Extent of T cell depletion was assessed by multiparameter fluorescent cell sorter (FACS) analysis and by functional studies. Cells staining positively by FACS analysis for one or more of three separate fluorescent pan-T cell monoclonal antibodies (MCAbs) comprised 8.4% to 9.5% of control marrow mononuclear cells (MNCs). T cells constituted 3.2% to 5.1% of marrow following single, sequential, or combination treatment with two different pan-T cell MCAbs (Leu 1 and TM1) plus complement, 1.5% to 2.2% of marrow following solid-phase immunoabsorption (“panning”), 0.2% of marrow after sheep cell rosetting, and only 0.05% of marrow after FACS selective cell sorting and gated separation. T cells made up 59% to 73% of control peripheral blood MNCs and 0.8% to 2.8% of peripheral MNCs following sheep cell rosetting plus treatment with Leu 1 MCAb and complement. Mitogen (PHA, Con A) and allogeneic MLC-induced blastogenic responses (stimulation indices, experimental/control or E/C) revealed a concordant decrement in marrow T cell function after MCAb plus complement (E/C of 3.9 to 9.0), after panning (E/C of 1.6 to 3.5) and after sheep cell rosetting (E/C of 0.7 to 1.3), compared with control marrow (E/C of 5.3 to 15.7). After T cell depletion, marrow BFU-E growth was 95% to 120% of control, CFU-GM growth was 90% to 108% of control, and CFU-GEMM growth was 89% to 111% of control. Marrow T cell and/or monocyte depletion did not alter erythropoietin-dependent BFU-E growth in the absence of Mo-conditioned medium (81% to 95% of control), and the addition of as many as 50 to 100 X 10(3) purified marrow monocytes or T cells to 10(5) autologous nonadherent T cell-depleted marrow target cells had a negligible (P greater than .1) effect on marrow BFU-E growth in vitro. Peripheral blood (PB) BFU-E/10(5) T- depleted target cells were 106% +/- 19% of expected; PB BFU-E growth was significantly diminished after monocyte depletion alone (7% +/- 6% of expected) or after monocyte plus T cell depletion (8% +/- 4% of expected).(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p&lt;0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p&lt;0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p&lt;.001; ATG/pTCD: 127±38, p&lt;.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

Abstract P143: Salt-sensitivity And Salt-resistance Differentially Modulate Renal And Colonic T Regulatory Cells

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Patrick A Molina ◽  
Claudia J Edell ◽  
Rachel Q Muir ◽  
Jackson C Colson ◽  
Craig L Maynard ◽  
...  
Keyword(s):  
T Cells ◽  
Drinking Water ◽  
T Cell ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
Salt Resistance ◽  
Functional Adaptation ◽  
Cell Populations ◽  
Protective Mechanisms ◽  
Host Protection

High salt diets (HSD) promote both inflammation and immunosuppression as shown in numerous studies utilizing salt-sensitive or hypertensive models. However, mechanisms involved in the homeostatic immune response to HSD, alone, have not been fully elucidated. Regulatory T cells (FOXP3 + CD4 + T cells) play a role in host protection against disease or environmental stressors. Further, recent studies show that RORt + expression by Tregs may represent a functional adaptation by Tregs in response to alterations to the diet. Thus, we hypothesized that these Treg populations may expand in response to HSD alone, and a hypertensive insult prior to the HSD blunts this response. We designed experiments to determine whether Tregs and RORt + Tregs expand in response to HSD or with LNAME hypertension followed by HSD. We evaluated the following groups in male C57BL/6J mice: NSD (normal salt diet, 0.4% NaCl), LNAME/NSD (0.5mg/ml for 3-wks in drinking water, followed by 3-wks NSD), HSD (4% NaCl+1% NaCl in drinking water, 2-wks), or LNAME/HSD (0.5mg/mL for 3-wks in drinking water, with 1-wk NSD followed by 2-wks HSD). Following immune cell isolation, we utilized flow cytometry to phenotype renal and colonic T cells. Data are expressed as frequency of means (% of CD4 + TCRbeta + T cells)±SEM (n=3-8/group) compared to NSD. In kidneys, HSD significantly expanded Tregs and RORt + Tregs, while LNAME/HSD group was unchanged compared to controls (% Treg: NSD: 5.7±0.5; L-NAME: 6.5±0.5; HSD: 9.2±1.0**; LNAME/HSD: 6.2±0.3; % RORt + Treg: NSD: 0.4±0.07; L-NAME: 0.6±0.13; HSD: 1.8±0.41***; LNAME/HSD: 0.6±0.14; **p<0.01, ***p<0.001). In the colon, HSD significantly expanded Tregs and RORt + Tregs, whereas the LNAME/HSD group had no change in these T cell populations (% Treg: NSD: 36±2; LNAME: 42±1; HSD: 46±2*; LNAME/HSD: 43±2; % RORt + Tregs: NSD: 16±1; LNAME: 19±1; HSD: 23±1*; LNAME/HSD: 20±2; *p<0.05). These data suggest that Tregs and RORt + Tregs expand in response to HSD in the kidney and colon, with a greater magnitude of expansion by RORt + Tregs. However, this expansion of T cell populations is not evident in mice pre-exposed to a hypertensive insult. We propose that HSD stimulates pathways that promote Treg expansion, which may be associated with salt-resistance and protective mechanisms.

scholarly journals In vitro tests for distinguishing possible immune-mediated aplastic anemia from transfusion-induced sensitization

Blood ◽  
1980 ◽  
Vol 55 (2) ◽  
pp. 211-215 ◽  
Author(s):  
BJ Torok-Storb ◽  
C Sieff ◽  
R Storb ◽  
J Adamson ◽  
ED Thomas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aplastic Anemia ◽  
Colony Growth ◽  
Cell Depletion ◽  
In Vitro Tests ◽  
T Cell Depletion ◽  
Immune Mediated ◽  
Before And After

Abstract Forty-two patients with aplastic anemia (AA) were studied to determine whether or not transfusion-induced sensitization is responsible for the in vitro inhibition by patient lymphocytes of HLA-identical erythroid burst-forming units (BFU-E). The results indicate that lymphocytes from 12 of 34 transfused patients inhibited normal colony growth. In contrast, lymphocytes from none of the 8 untransfused patients demonstrated inhibition. These data were interpreted to mean that coculture studies would not be useful for identifying immune-mediated AA in transfused patients. Therefore, in order to identify possible immune-related AA, we assayed BFU-E from patient blood before and after T-cell depletion. In all 32 patients studied, BFU-E failed to grow from peripheral blood cells before T-cell depletion, but in 8 cases, normal- appearing BFU-E grew after T cells had been removed. Growth of patient BFU-E colonies was inhibited in 6 cases when patient T cells were added back to the culture, indicating that in these 6 patients, an “autoimmune” mechanism may have been present.

scholarly journals CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Yutao Wang ◽  
Kexin Yan ◽  
Jiaxing Lin ◽  
Yang Liu ◽  
Jianfeng Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mhc Class I ◽  
Clinical Phenotype ◽  
Angiogenesis Inhibitors ◽  
Class I ◽  
T Cell Infiltration ◽  
Tumor Purity

PurposeTo identify immune-related co-expressed genes that promote CD8+ T cell infiltration in bladder cancer, and to explore the interactions among relevant genes in the tumor microenvironment.MethodWe obtained bladder cancer gene matrix and clinical information data from TCGA, GSE32894 and GSE48075. The “estimate” package was used to calculate tumor purity and immune score. The CIBERSORT algorithm was used to assess CD8+ T cell proportions. Weighted gene co-expression network analysis was used to identify the co-expression modules with CD8+ T cell proportions and bladder tumor purity. Subsequently, we performed correlation analysis among angiogenesis factors, angiogenesis inhibitors, immune inflammatory responses, and CD8+ T cell related genes in tumor microenvironment.ResultsA CD8+ T cell related co-expression network was identified. Eight co-expressed genes (PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, and were enriched in the MHC class I tumor antigen presentation process. The proteins level encoded by these genes (PSMB10, PSMB9, PSMB8, TAP1, IRF1, and FBXO6) were lower in the high clinical grade patients, which suggested the clinical phenotype correlation both in mRNA and protein levels. These factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. PD-1 and PD-L1 positively correlated with these genes which suggested PD-1 expression level positively correlated with the biological process composed by these co-expression genes. In the high expression group of these genes, inflammation and immune response were more intense, and the tumor purity was lower, suggesting that these genes were immune protective factors that improved the prognosis in patients with bladder cancer.ConclusionThese co-expressed genes promote high levels of infiltration of CD8+ T cells in an immunoproteasome process involved in MHC class I molecules. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

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