TAMI-58. TARGETING GLIOBLASTOMA BY ACTIVATING VIRAL SPECIFIC TISSUE-RESIDENT MEMORY T CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi210-vi210
Author(s):  
Jianfang Ning ◽  
Noah Gavil ◽  
Shaoping Wu ◽  
Jun Ma ◽  
Ming Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Memory T Cells ◽  
Tumor Development ◽  
Intratumoral Injection ◽  
Adult Brain ◽  
Cell Subpopulation ◽  
T Cell Epitopes ◽  
Peripheral Tissues

Abstract Immunotherapy with the success of checkpoint blockade brings hope for cancer treatment with enduring or complete responses in various types of advanced malignancies, however, it has not benefited a number of so called “cold tumors”, such as glioblastoma multiforme (GBM), the most common and aggressive adult brain cancer. GBM is invariably lethal with a median survival of less than 15 months and characterized by a highly immunosuppressive tumor microenvironment, which desires new means of GBM immune-reactivation. Tissue-resident memory CD8+ T (TRM) cells are non-recirculating memory T cell subpopulation that resides permanently in peripheral tissues. TRM cells provide long-lived protective immunity against not only local pathogen infection but also tumor development through immediate effector function and recruitment of circulating immune cells upon antigen re-exposure. In this study, we found that memory T cells specific to some common human viruses that have infected almost everybody exist in clinical GBM specimens and can be activated by viral peptides, which are MHC I restricted CD8+ T cell epitopes derived from those viruses. In orthotopic GBM immunocompetent mouse models, we detected abundant virus specific TRM cells in the tumor microenvironment of GBMs intracranially established in mice that were previously exposed to the virus. Excitingly, intratumoral injection of viral peptides stimulated the reactivation of TRM cells, indicated by secretion of immuno-stimulatory cytokines, and demonstrated significant anti-tumor efficacy. This study provides proof of principle for TRM cell-based GBM therapy, which is a novel therapeutic paradigm with the translational potential for this deadly malignancy.

scholarly journals 778 Modulating tumor microenvironment with arginase-1 specific T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A813-A813
Author(s):  
Evelina Martinenaite ◽  
Mia Aaboe Jørgensen ◽  
Rasmus Erik Johansson Mortensen ◽  
Shamaila Munir Ahmad ◽  
Stine Emilie Weis-Banke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Memory T Cells ◽  
Ethics Committee ◽  
Mouse Tumor ◽  
Immune Modulators ◽  
Arginase 1 ◽  
Mouse Tumor Models

BackgroundIO112 is an immune modulatory cancer therapy under preclinical development to target arginase-1-expressing tumor cells and immune inhibitory myeloid cells, such as myeloid derived suppressor cells (MDSCs), and tumor associated macrophages (TAMs). Arginase-1 acts as a metabolic immune regulator at the tumor site by reducing availability of L-arginine to the infiltrating immune cells thus reducing T cell functionality and proliferation. Previously, we demonstrated that IO112 triggers activation of spontaneous CD4+ and CD8+ T-cell responses against arginase-1, found in both cancer patients and healthy individuals.1 These T cells are present in the memory T cell compartment, and are activated in arginase-1 inducing conditions, such as presence of TH2 cytokines IL-4 or IL-13 in vitro.2 3 In this study we aimed to explore the role of arginase-1-specific T cells as immune modulators in immune homeostasis and tumor microenvironment for the development of IO112 immunomodulatory therapy.MethodsHuman arginase-1-specific T cells were isolated and expanded for functional characterization of reactivity against arginase-1 expressing target cells as well as subsequent phenotyping of the targeted arginase-1 positive cells. Syngeneic C57BL/6 mouse tumor models were used to assess the therapeutic efficacy of IO112.ResultsWe show that arginase-1-specific memory T cells specifically recognize arginase-1 expressing cells, such as mRNA transfected autologous dendritic cells (DCs) and B cells as well as M2 polarized macrophages in vitro. In addition, activated arginase-1-specific T cells produce pro-inflammatory cytokines IFNγ and TNFα. Secretion of TH1 cytokines by these T cells suggests that they may act as potent immune modulators in the tumor microenvironment, since many arginase-1 expressing myeloid cells are not terminally differentiated and they can be re-polarized to an immunostimulatory, M1-like phenotype. We also observed that targeting of M2-polarized arginase-1 expressing monocytic leukemia cell line THP-1 with arginase-1-specific CD4+ T cells induces upregulation of PD-L1 on the THP-1 cells. Furthermore, we demonstrate anti-tumor activity of IO112 in syngeneic mouse tumor models (B16 and MC38), both as monotherapy and in combination with anti-PD-1 treatment. The therapeutic effect was associated with increased immune infiltration in the IO112-treated mice compared to the control.ConclusionsWe demonstrate that arginase-1 specific T cells can influence the polarization of arginase-1-expressing immune cells. Our study provides evidence that IO112 immune therapy against arginase-1 is an attractive way of modulating the immune suppressive tumor microenvironment for therapeutic benefit. With this rationale, we are currently undertaking Investigational New Drug (IND) application enabling studies to explore this approach in a clinical setting.ReferencesMartinenaite E, Mortensen REJ, Hansen M, Holmström MO, Ahmad SM, Jørgensen NGD, Met Ö, Donia M, Svane IM, Andersen MH. Frequent adaptive immune responses against arginase-1. Oncoimmunology 2018;7(3):e1404215.Martinenaite E, Ahmad SM, Svane IM, Andersen MH. Peripheral memory T cells specific for Arginase-1. Cell Mol Immunol 2019;16(8):718–719.Martinenaite E, Ahmad SM, Bendtsen SK, Jørgensen MA, Weis-Banke SE, Svane IM, Andersen MH. Arginase-1-based vaccination against the tumor microenvironment: the identification of an optimal T-cell epitope. Cancer Immunol Immunother 2019;68(11):1901–1907.Ethics ApprovalThis study was approved by the Scientific Ethics Committee for The Capital Region of Denmark and Danish Ethics Committee on experimental animal welfare.

scholarly journals THE LYMPHOCYTE RESPONSE TO PRIMARY MOLONEY SARCOMA VIRUS TUMORS IN BALB/c MICE

1973 ◽  
Vol 137 (6) ◽  
pp. 1472-1493 ◽  
Author(s):  
E. W. Lamon ◽  
H. Wigzell ◽  
E. Klein ◽  
B. Andersson ◽  
H. M. Skurzak
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Iron Powder ◽  
Cell Activity ◽  
Tumor Development ◽  
Cell Subpopulation ◽  
Target Cells ◽  
Sarcoma Virus ◽  
Moloney Sarcoma Virus

Adult BALB/c mice were injected with Moloney sarcoma virus (MSV) after which the animals' lymphocytes were examined for activity against Moloney leukemia virus (MLV) antigen-bearing target cells at 5-day intervals for 30 days. Lymphocytes from these animals and appropriately matched controls were fractionated into B cell-deficient (primarily T cells) and T cell-deficient (primarily B cells) subpopulations. Macrophages were removed using iron powder and magnetism. The unfractionated lymphocytes, T cells, and non-T cells were then tested in microcytotoxicity tests. Antigen-specific activity was found in the unfractionated lymphocytes from animals that had not yet developed palpable tumors and from regressor animals. The T cells were active just before tumor development and just after regression; however, by day 30 after virus infection (8–10 days after regression) the T cell subpopulation was much less active. The non-T cell subpopulation was also active before tumor development and soon after regression. However, this activity continued to rise after regression and was highest at 30 days. At day 15 (peak tumor size) neither subpopulation was active. The activity was demonstrated to be specific for the MLV-determined cell surface antigen by testing on control target cells that were MLV antigen negative and by comparison of the inhibitory effects with lymphocytes immune to a nonpertinent antigen as well as normal lymphocytes. The non-T cells were tested for activity before and after removal of macrophages with iron powder and magnetism. Such cells were significantly more active after removal of the macrophages. These data demonstrate specific T cell and non-T cell activity in microcytotoxicity tests with a tumor-specific system and strongly suggest that the non-T cell activity described herein is a B cell function.

scholarly journals IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)

2018 ◽  
Vol 20 (5) ◽  
pp. 613-620
Author(s):  
E. K. Oleinik ◽  
A. V. Churov ◽  
V. M. Oleinik
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Structural Organization ◽  
Memory T Cells ◽  
Treg Cells ◽  
T Cell Memory ◽  
Peripheral Tissues

Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system.

scholarly journals The evolution of T-cell receptor repertoire in different stages of non-small cell lung cancer

2020 ◽  
Author(s):  
Ziqi Jia ◽  
Yadong Wang ◽  
Xiaoying Yang ◽  
Pancheng Wu ◽  
Yanyu Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Background The intricate relationship between the tumor and host was not well understood, and antigen-specific T cell is fundamental in understanding the interaction. TCR repertoire analysis which described TCR clonotypes and TCR numbers has shown that TCRs with high frequency was tumor-specific T cells, while others might be ‘bystander’ T cells within tumors. However, how these “expanded” tumor-specific T cells was selected during the tumor development was not clear. Methods We retrospectively analyzed TCR sequencing and mutation sequencing results from 144 non-small cell lung cancer (NSCLC) patients. Results A rich TCR repertoire comprising thousands of different TCR sequences was identified in all stages of NSCLC, with most TCR clonotypes presented at low frequency. Interestingly, Stage IV NSCLC tumors contain more expanded TCRs as compared to earlier stages, however, lymph node metastasis or tumor size had little impact on expanded TCRs. Moreover, accumulation of mutations did not significantly change the number of TCR clonotypes, however, EGFR mutant patients had significantly lower while KRAS mutant patients had significantly higher number of TCR clonotypes especially in terms of those “expanded” TCRs. Conclusions In summary, T cells in the tumor microenvironment were gradually activated with tumor development. Critical events such as distal metastases and generation of EGFR or KRAS mutations might be the major factors affecting the changing of tumor-specific T cells in the tumor microenvironment.

scholarly journals Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma

2021 ◽  
Vol 22 (23) ◽  
pp. 12933
Author(s):  
Shuichi Nakai ◽  
Eiji Kiyohara ◽  
Rei Watanabe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoid Tissues ◽  
Cutaneous T Cell Lymphoma ◽  
Malignant Cells ◽  
Peripheral Tissues ◽  
Malignant T Cells

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (TRM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (TCM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells.

scholarly journals Solid Tumor Microenvironment Can Harbor and Support Functional Properties of Memory T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Peter M. Sullivan ◽  
Steven James Reed ◽  
Vandana Kalia ◽  
Surojit Sarkar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Solid Tumor ◽  
Memory T Cells ◽  
T Cell Responses ◽  
Antigenic Stimulation ◽  
Cell Responses

Robust T cell responses are crucial for effective anti-tumor responses and often dictate patient survival. However, in the context of solid tumors, both endogenous T cell responses and current adoptive T cell therapies are impeded by the immunosuppressive tumor microenvironment (TME). A multitude of inhibitory signals, suppressive immune cells, metabolites, hypoxic conditions and limiting nutrients are believed to render the TME non-conducive to sustaining productive T cell responses. In this study we conducted an in-depth phenotypic and functional comparison of tumor-specific T cells and tumor-nonspecific bystander memory T cells within the same TME. Using two distinct TCR transgenic and solid-tumor models, our data demonstrate that despite exposure to the same cell-extrinsic factors of the TME, the tumor-nonspecific bystander CD8 T cells retain the complete panoply of memory markers, and do not share the same exhaustive phenotype as tumor-reactive T cells. Compared to tumor-specific T cells, bystander memory CD8 T cells in the TME also retain functional effector cytokine production capabilities in response to ex vivo cognate antigenic stimulation. Consistent with these results, bystander memory T cells isolated from tumors showed enhanced recall responses to secondary bacterial challenge in a T cell transplant model. Importantly, the tumor-resident bystander memory cells could also efficiently utilize the available resources within the TME to elaborate in situ recall effector functions following intra-tumoral peptide antigen injection. Additionally, CRISPR-Cas9 gene deletion studies showed that CXCR3 was critical for the trafficking of both tumor antigen-specific and bystander memory T cells to solid tumors. Collectively, these findings that T cells can persist and retain their functionality in distinct solid tumor environments in the absence of cognate antigenic stimulation, support the notion that persistent antigenic signaling is the central driver of T cell exhaustion within the TME. These studies bear implications for programming more efficacious TCR- and CAR-T cells with augmented therapeutic efficacy and longevity through regulation of antigen and chemokine receptors.

Human CD62L– memory T cells are less responsive to alloantigen stimulation than CD62L+ naive T cells: potential for adoptive immunotherapy and allodepletion

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2403-2409 ◽  
Author(s):  
Aaron E. Foster ◽  
Marina Marangolo ◽  
Mary M. Sartor ◽  
Stephen I. Alexander ◽  
Min Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Donor Cell ◽  
Cell Receptor ◽  
Cell Subpopulation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Barr Virus

Abstract Selective depletion of alloreactive T cells from allogeneic stem cell grafts can reduce graft-versus-host disease (GVHD) while preserving beneficial effects of T cells including facilitation of engraftment, protection against opportunistic infection, and reduced relapse risk. Memory T cells (CD62L–) represent a population of T cells that have previously encountered pathogens and may contain fewer T cells capable of recognizing neoantigens including recipient allogeneic antigen (aAg). We investigated whether human naive (CD62L+) or memory (CD62L–) T cells had different capacities to respond to aAg by assessing their ability to proliferate in response to and lyse HLA-mismatched Epstein-Barr virus–transformed B cells. Freshly sorted and in vitro expanded CD62L– memory T cells were less responsive to aAg stimulation than were CD62L+ naive T cells but contained higher levels of cytomegalovirus (CMV)–specific T cells. Analysis of T cell receptor (TCR) repertoire showed restricted TCR diversity in the memory T-cell population possibly due to selection associated with chronic exposure to common pathogens. Memory T cells may represent a donor cell subpopulation suitable for enhancing immune reconstitution without increasing the risk of GVHD.

scholarly journals Memory T Cells Specific for Novel Human Papillomavirus Type 16 (HPV16) E6 Epitopes in Women Whose HPV16 Infection Has Become Undetectable

2008 ◽  
Vol 15 (6) ◽  
pp. 937-945 ◽  
Author(s):  
Xuelian Wang ◽  
Anna-Barbara Moscicki ◽  
Laura Tsang ◽  
Andrea Brockman ◽  
Mayumi Nakagawa
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Viral Clearance ◽  
T Cell Epitopes ◽  
Hpv16 E6 ◽  
Specific Memory ◽  
E6 Protein

ABSTRACT Human papillomavirus (HPV)-specific T-cell response to the HPV type 16 (HPV16) E6 protein has been shown to be associated with successful viral clearance. The patterns of CD8 T-cell epitopes within HPV16 E6 protein were previously studied in two women with HPV16 clearance. The goal of this study was to characterize these epitopes in terms of their minimal and optimal amino acid sequences and the human leukocyte antigen (HLA) restriction molecules. The presence of the epitope-specific memory T cells after viral clearance was also examined. In subject A, the dominant epitope was characterized to be E6 75-83 (KFYSKISEY), restricted by the HLA-B62 molecule, while that of subject B was E6 133-142 (HNIRGRWTGR), restricted by the HLA-A6801 molecule. Homologous epitopes were identified in five other high-risk HPV types for both of these epitopes, but they were not recognized by respective T-cell clone cells. An enzyme-linked immunospot assay or tetramer analysis was performed on peripheral blood mononuclear cells from blood samples collected after viral clearance but prior to isolation of the T-cell clones. The presence of epitope-specific memory T cells was demonstrated. These data suggest that HPV-specific memory T cells were generated in vivo and that they may remain in circulation many months, if not years, after viral clearance. Our findings broaden the spectrum of the CD8 T-cell epitopes of the HPV16 E6 protein. The characterization of novel T-cell epitopes and long-lasting epitope-specific memory T cells may be useful for the development of a potential epitope-based vaccine.

scholarly journals Clinical Significance of Shared T Cell Epitope Analysis in Early De Novo Donor-Specific Anti-HLA Antibody Production After Kidney Transplantation and Comparison With Shared B cell Epitope Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Toshihide Tomosugi ◽  
Kenta Iwasaki ◽  
Shintaro Sakamoto ◽  
Matthias Niemann ◽  
Eric Spierings ◽  
...  
Keyword(s):  
T Cells ◽  
Kidney Transplantation ◽  
T Cell ◽  
De Novo ◽  
Memory T Cells ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
Hla Antibodies ◽  
Epitope Analysis ◽  
Hla Antibody

In pre-sensitizing events, immunological memory is mainly createdviaindirect allorecognition where CD4+T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using anin silicoassay, an alternative to estimate donor-reactive CD4+memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+memory T cells.De novoDSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+memory T cells may help predict the risk of earlyde novoDSA formation after kidney transplantation.

scholarly journals The Development, Function, and Plasticity of the Immune Macroenvironment in Cancer

2019 ◽  
Author(s):  
Breanna M. Allen ◽  
Kamir J. Hiam ◽  
Cassandra E. Burnett ◽  
Anthony Venida ◽  
Rachel DeBarge ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Resection ◽  
Tumor Development ◽  
T Cell Responses ◽  
Immune Defense ◽  
Peripheral Tissues ◽  
Cell Responses

ABSTRACTHarnessing immune defense mechanisms has revolutionized cancer therapy, but our understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. Here, we use mass cytometry to define the organism-wide immune landscape in response to tumor development across five tissues in eight tumor models. Systemic immunity was dramatically altered across mouse models and cancer patients, with changes in peripheral tissues differing from those in the tumor microenvironment and taking place in phases during tumor growth. This tumor-experienced immune system mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Disruptions in T cell responses were not cell-intrinsic but rather due to reduced responses in antigen-presenting cells (APCs). Promoting APC activation was sufficient to restore T cell responses to orthogonal infection. All systemic immune changes were reversed with surgical tumor resection, revealing remarkable plasticity in the systemic immune state, which contrasts with terminal immune dysfunction in the tumor microenvironment. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.

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