scholarly journals Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and systemic intratumoral T-cell activity

2018 ◽  
Author(s):  
Paula Kroon ◽  
Elselien Frijlink ◽  
Victoria Iglesias-Guimarais ◽  
Andriy Volkov ◽  
Marit M van Buuren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Tumor Control ◽  
Cancer Treatments ◽  
Costimulatory Receptor ◽  
Breast Cancer Model ◽  
Mouse Breast Cancer ◽  
Summary Statement

AbstractTo increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined in a poorly immunogenic mouse breast cancer model the potential of antibody-based immunomodulation and conventional anti-cancer treatments to collaborate with anti-PD-1 treatment. One important requirement to improve anti-PD-1-mediated tumor control was to promote tumor-specific cytotoxic T cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1-unrelated mechanisms of CTL suppression in the tumor micro-environment (TME). This was achieved by radiotherapy and cisplatin treatment. In the context of CD137/PD-1-targeting immunotherapy, radiotherapy allowed for tumor elimination by altering the TME, rather than intrinsic CTL functionality. Combining this radioimmunotherapy regimen with low-dose cisplatin improved CTL-dependent regression of a contralateral tumor outside the radiation field. Thus, systemic tumor control may be achieved by combining immunotherapy protocols that promote T cell priming with (chemo)radiation protocols that permit CTL activity in both the irradiated tumor and (occult) metastases.Summary statementThis study reveals that radiotherapy and cisplatin can be ‘re-purposed’ to improve antibody-based immunotherapy success in poorly immunogenic breast cancer by overruling PD-1 unrelated mechanisms of T cell suppression in the tumor micro-environment.

scholarly journals IL-31 induces antitumor immunity in breast carcinoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001010
Author(s):  
Tal Kan ◽  
Erik Feldman ◽  
Michael Timaner ◽  
Ziv Raviv ◽  
Shai Shen-Orr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Breast Carcinoma ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Therapeutic Activity

BackgroundImmunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer.MethodsIn vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity.ResultsThe growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model.ConclusionsOur findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.

scholarly journals An inducible transgenic mouse breast cancer model for the analysis of tumor antigen specific CD8+ T-cell responses

Oncotarget ◽  
2015 ◽  
Vol 6 (36) ◽  
pp. 38487-38503 ◽  
Author(s):  
Michael Bruns ◽  
Jara Wanger ◽  
Olaf Utermöhlen ◽  
Wolfgang Deppert
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Transgenic Mouse ◽  
Tumor Antigen ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cancer Model ◽  
Cell Responses ◽  
Breast Cancer Model ◽  
Mouse Breast Cancer

scholarly journals Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Yufan Qiu ◽  
Yi Yang ◽  
Riyao Yang ◽  
Chunxiao Liu ◽  
Jung-Mao Hsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cell Surface ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Cell Contact ◽  
Activated T Cells ◽  
Positive Role

AbstractProgrammed cell death 1 (PD-1) is widely expressed in tumor-infiltrating lymphocytes (TILs) of triple-negative breast cancer (TNBC). As a dominant inhibitory immune checkpoint (ICP) receptor, cell surface PD-1 is well-known to transduce negative signaling of effector T cell activity during cell–cell contact. However, despite its well-documented inhibitory effects, higher PD-1 expression in TILs is significantly associated with longer survival in TNBC patients. This phenomenon raises an interesting question whether PD-1 harbors positive activity to enhance anti-tumor immunity. Here, we show that PD-1 is secreted in an exosomal form by activated T cells and can remotely interact with either cell surface or exosomal programmed death-ligand 1 (PD-L1), induce PD-L1 internalization via clathrin-mediated endocytosis, and thereby prevent subsequent cellular PD-L1: PD-1 interaction, restoring tumor surveillance through attenuating PD-L1-induced suppression of tumor-specific cytotoxic T cell activity. Our results, through revealing an anti-PD-L1 function of exosomal PD-1, provide a positive role to enhance cytotoxic T cell activity and a potential therapeutic strategy of modifying the exosome surface with membrane-bound inhibitory ICP receptors to attenuate the suppressive tumor immune microenvironment.

scholarly journals A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jeremy To ◽  
Doug Quackenbush ◽  
Emily Rowell ◽  
Lilin Li ◽  
Connor Reed ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Dependent Manner ◽  
Cyclin Dependent Kinase ◽  
Histocompatibility Complex ◽  
T Cell Function ◽  
Cytolytic Granule ◽  
Screening Platform

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

scholarly journals Characterization of human T cells reactive with the Mycoplasma arthritidis-derived superantigen (MAM): generation of a monoclonal antibody against V beta 17, the T cell receptor gene product expressed by a large fraction of MAM-reactive human T cells.

1991 ◽  
Vol 174 (4) ◽  
pp. 891-900 ◽  
Author(s):  
S M Friedman ◽  
M K Crow ◽  
J R Tumang ◽  
M Tumang ◽  
Y Q Xu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Activity ◽  
Cell Receptor ◽  
Cytotoxic T Cell ◽  
Mycoplasma Arthritidis ◽  
Human T Cells

While all known microbial superantigens are mitogenic for human peripheral blood lymphocytes (PBL), the functional response induced by Mycoplasma arthritidis-derived superantigen (MAM) is unique in that MAM stimulation of PBL consistently results in T cell-dependent B cell activation characterized by polyclonal IgM and IgG production. These immunostimulatory effects of MAM on the humoral arm of the human immune system warranted a more precise characterization of MAM-reactive human T cells. Using an uncloned MAM reactive human T cell line as immunogen, we have generated a monoclonal antibody (mAb) (termed C1) specific for the T cell receptor V beta gene expressed by the major fraction of MAM-reactive human T cells, V beta 17. In addition, a V beta 17- MAM-reactive T cell population exists, assessed by MAM, induced T cell proliferation and cytotoxic T cell activity. mAb C1 will be useful in characterizing the functional properties of V beta 17+ T cells and their potential role in autoimmune disease.

scholarly journals Skin test to assess virus-specific cytotoxic T-cell activity.

1992 ◽  
Vol 89 (16) ◽  
pp. 7757-7761 ◽  
Author(s):  
T. M. Kundig ◽  
A. Althage ◽  
H. Hengartner ◽  
R. M. Zinkernagel
Keyword(s):  
T Cell ◽  
Skin Test ◽  
Cell Activity ◽  
Cytotoxic T Cell

scholarly journals Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
L. Berrueta ◽  
J. Bergholz ◽  
D. Munoz ◽  
I. Muskaj ◽  
G. J. Badger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Model ◽  
Breast Cancer Model ◽  
Mouse Breast Cancer
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