scholarly journals ADHESION CONCEPT IN CANCER BIOLOGY: LOCAL AND CENTRAL MECHANISMS (PART 1)

2021 ◽  
Vol 20 (3) ◽  
pp. 17-24
Author(s):  
O. A. Bocharova ◽  
V. B. Matveev ◽  
E. V. Bocharov ◽  
R. V. Karpova ◽  
V. G. Kucheryanu
Keyword(s):  
Tumor Cells ◽  
Adhesion Molecules ◽  
Cancer Biology ◽  
Genetic Mutation ◽  
Target Cells ◽  
Β2 Integrin ◽  
Leukocyte Integrins ◽  
Proliferation And Differentiation ◽  
Β1 Integrins ◽  
Integrin Family

The review presents the concept the key mechanism of the tumor process is a violation of adhesion interactions involving local and central mechanisms. Local features of adhesive dysregulation are demonstrated in the first part. The lack of histospecific adhesion molecules expression resulting from stress or genetic mutation damages an important mechanism of antitumor protection of the tissue disrupting the processes of proliferation and differentiation. The deficiency of histone-specific homotypic adhesion molecules which occurs later exacerbates the disorders. This leads to a decrease in the expression of leukocyte integrins (LFA-1, Mac-1) ligands of the β2 family on the surface of immune effectors and to an increase also in the expression of adhesion molecules to the substrate-antigens VLA (very late activation) family of β1 -integrins on tumor cells. The first restricts the interaction of ICAM family molecules with their contra-receptors from the β2 -integrin family reducing the elimination of target cells by immune effectors which contributes to the screening of the tumor from antitumor surveillance. The second promotes the invasion of the tumor into the surrounding tissues, the formation of blood vessels as well as its heterotypic adhesion with other tissues which further stimulates the proliferation and suppression processes of tumor cells apoptosis. So, the adhesion molecules can be compared to the Phoenix bird: disappearing at the beginning of the process (between the similar cells), they reappear in a new quality (increasing adhesion to cells of other tissues), increasing the totalysm of the tumor. It should be taken into account that tumor cells due to adhesion dysregulation “isolate themselves from society”, lose their differentiation, their maturity and “fall into childhood”, being unable to perform specific, “adult” functions. So, cancer can be considered as a manifestation of the cells aging. Therefore, the anti-stress, endogenous geroprotective mechanisms activation based on the adhesion correction can be effective for preventing and treatment the oncological process. 

scholarly journals Costimulation by B7 Modulates Specificity of Cytotoxic T Lymphocytes: A Missing Link That Explains Some Bystander T Cell Activation

1997 ◽  
Vol 186 (10) ◽  
pp. 1787-1791 ◽  
Author(s):  
Pan Zheng ◽  
Yang Liu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Target Cells ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

It has been proposed that some bystander T cell activation may in fact be due to T cell antigen receptor (TCR) cross-reactivity that is too low to be detected by the effector cytotoxic T lymphocyte (CTL). However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL. Here we report that transgenic T cells expressing a T cell receptor to influenza virus A/NT/68 nucleoprotein (NP) 366-374:Db complexes clonally expand and become effector CTLs in response to homologous peptides from either A/PR8/34 (H1N1), A/AA/60 (H2N2), or A/NT/68 (H3N2). However, the effector T cells induced by each of the three peptides kill target cells pulsed with NP peptides from the H3N2 and H2N2 viruses, but not from the H1N1 virus. Thus, NP366–374 from influenza virus H1N1 is the first TCR ligand that can induce T cell proliferation and differentiation without being recognized by CTLs. Since induction of T cell proliferation was mediated by antigen-presenting cells that express costimulatory molecules such as B7, we investigated if cytolysis of H1N1 NP peptide–pulsed targets can be restored by expressing B7-1 on the target cells. Our results revealed that this is the case. These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

scholarly journals Human Dendritic Cells Mediate Cellular Apoptosis via Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail)

1999 ◽  
Vol 190 (8) ◽  
pp. 1155-1164 ◽  
Author(s):  
Neil A. Fanger ◽  
Charles R. Maliszewski ◽  
Ken Schooley ◽  
Thomas S. Griffith
Keyword(s):  
Dendritic Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Target Cells ◽  
Functional Difference ◽  
Cellular Apoptosis ◽  
Soluble Trail ◽  
Innate Effector ◽  
Human Dendritic Cells ◽  
Necrosis Factor

TRAIL (TNF-related apoptosis-inducing ligand) is a member of the TNF family that induces apoptosis in a variety of cancer cells. In this study, we demonstrate that human CD11c+ blood dendritic cells (DCs) express TRAIL after stimulation with either interferon (IFN)-γ or -α and acquire the ability to kill TRAIL-sensitive tumor cell targets but not TRAIL-resistant tumor cells or normal cell types. The DC-mediated apoptosis was TRAIL specific, as soluble TRAIL receptor blocked target cell death. Moreover, IFN-stimulated interleukin (IL)-3 receptor (R)α+ blood precursor (pre-)DCs displayed minimal cytotoxicity toward the same target cells, demonstrating a clear functional difference between the CD11c+ DC and IL-3Rα+ pre-DC subsets. These results indicate that TRAIL may serve as an innate effector molecule on CD11c+ DCs for the elimination of spontaneously arising tumor cells and suggest a means by which TRAIL-expressing DCs may regulate or eliminate T cells responding to antigen presented by the DCs.

scholarly journals Granzyme B Is a Biomarker for Suspicion of Malignant Seromas Around Breast Implants

2020 ◽  
Author(s):  
Marshall E Kadin ◽  
John Morgan ◽  
Haiying Xu ◽  
Caroline Glicksman ◽  
David Sieber ◽  
...  
Keyword(s):  
Early Detection ◽  
Tumor Cells ◽  
Breast Implant ◽  
Granzyme B ◽  
Breast Implants ◽  
Large Cell ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Tumor Cell Death ◽  
Level Of Evidence

Abstract Background Granzyme B (GrB) is a serine protease secreted, along with pore-forming perforin, by cytotoxic lymphocytes to mediate apoptosis in target cells. GrB has been detected in tumor cells associated with systemic and breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) but its potential use for detection of early BIA-ALCL has not been fully investigated. Objectives Prompted by the increased incidence of BIA-ALCL, the aim of this study was to assess GrB as a new biomarker to detect early disease in malignant seromas and to better understand the nature of the neoplastic cell. Methods A Human XL Cytokine Discovery Magnetic Luminex 45-plex Fixed Panel Performance Assay was used to compare cytokine levels in cell culture supernatants of BIA-ALCL and other T-cell lymphomas, as well as malignant and benign seromas surrounding breast implants. Immunohistochemistry was employed to localize GrB to cells in seromas and capsular infiltrates. Results Differences in GrB concentrations between malignant and benign seromas were significant (P < 0.001). GrB was found in and around apoptotic tumor cells, suggesting that the protease may be involved in tumor cell death. Conclusions GrB is a useful marker for early detection of malignant seromas and to identify tumor cells in seromas and capsular infiltrates. Because there is an overlap between the lowest concentrations of soluble GrB in malignant seromas and the highest concentrations of GrB in benign seromas, it is recommended that GrB be used only as part of a panel of biomarkers for the screening and early detection of BIA-ALCL. Level of Evidence: 5

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Annette Paschen ◽  
Ignacio Melero ◽  
Antoni Ribas
Keyword(s):  
Antigen Presentation ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Cancer Biology ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Class I ◽  
Annual Review ◽  
Publication Date ◽  
Type I

Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models, potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Tumor cell anti-oxidant defenses. Inhibition of the glutathione redox cycle enhances macrophage-mediated cytolysis

1981 ◽  
Vol 153 (4) ◽  
pp. 766-782 ◽  
Author(s):  
CF Nathan ◽  
BA Arrick ◽  
HW Murray ◽  
NM DeSantis ◽  
ZA Cohm
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Defense Mechanisms ◽  
Specific Activity ◽  
Protective Role ◽  
Target Cells ◽  
Redox Cycle ◽  
Oxidation Reduction ◽  
Glutathione Redox Cycle ◽  
Glutathione Redox

The basis of resistance to oxidative injury was studied in six murine tumor cell lines that differed 54-fold in their resistance to enzymatically generated H(2)0(2). The tumors varied 56.7-fold in their specific activity of catalase, 5.3-fold in glutathione peroxidase (GPO), 3.3-fold in glutathione reductase (GR), and 2.7-fold in glutathione. There was no correlation among the levels of the three enzymes, and tumor cell resistance to lysis by H(2)0(2). However, the logarithm of the flux of H(2)0(2) necessary to cause 50 percent lysis of the tumor cells correlated with their content of glutathione (r = 0.91). The protective role of glutathione was analyzed by blocking GR and GPO, the catalysts of the glutathione redox cycle. This was facilitated by the demonstration that the anti-neoplastic agent 1,3-bis-(2- chloroethyl)-l-nitrosourea (BCNU) was a potent inhibitor of GR in intact tumor cells. BCNU inactivated tumor cell GR with a 50 percent inhibitory dose of 11 μM and a t(l/2) of inhibition of 30 s. Complete inhibition of GR was attained with no effect on GPO or catalase. Tumor cells whose GR was inactivated by BCNU could be lysed by fluxes of H(2)0(2) to which they were otherwise completely resistant. They could be killed by phorbol myristate acetate (PMA)-stimulated, bacilli Calmette-Guerin-activated macrophages in numbers which were otherwise insufficient, and by nonactivated macrophages, which otherwise were ineffective. BCNU-treated target cells were also much more sensitive to antibody-dependent, macrophage-mediated cytolysis. However, such tumor cells were no more sensitive than controls to lysis by alloreactive T cells or by antibody plus complement. Next, we deprived tumor cells of selenium by passage in selenium-deficient mice. GPO was inhibited 85 percent in such cells, with no effect on GR or catalase. Tumor cells with reduced GPO activity were markedly sensitized to lysis by small fluxes of H(2)0(2) or by PMA-stimulated macrophages or granulocytes. In contrast, inhibition of catalase with aminotriazole had no effect on the sensitivity of three tumors to peroxide-mediated lysis, and had modest effects with two others. Thus, the oxidation-reduction cycle of glutathione serves as one of the major defense mechanisms of tumor cells against three related forms of oxidant injury: lysis by fluxes of H(2)0(2), by PMA-triggered macrophages, and by macrophages in the presence of anti-tumor antibody.

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals EXPRESSION OF NEURAL CELL ADHESION MOLECULES IN THE MOUSE ANTERIOR PITUITARY GLAND AND PITUITARY TUMOR CELLS

1998 ◽  
Vol 19 (4) ◽  
pp. 269-277
Author(s):  
YOSHIHIRO YAYOI ◽  
SUMIO TAKAHASHI ◽  
SAKAE TAKEUCHI ◽  
MAKOTO TAKEUCHI ◽  
TATSUNORI SEKI ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pituitary Gland ◽  
Tumor Cells ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Pituitary Tumor ◽  
Anterior Pituitary ◽  
Neural Cell ◽  
Neural Cell Adhesion Molecules ◽  
Neural Cell Adhesion

scholarly journals 894 The bispecific innate cell engagers AFM13 (CD30/CD16A) and AFM24 (EGFR/CD16A) increase the fraction of tumor target-responsive NK cells and boost serial killing

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A938-A938
Author(s):  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Christian Breunig ◽  
...  
Keyword(s):  
Nk Cells ◽  
Single Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Nk Cell ◽  
Biological Evaluation ◽  
Target Cells ◽  
List Type ◽  
Tumor Target ◽  
Serial Killing

BackgroundThe use of bispecific natural killer (NK) cell engagers has emerged as a successful strategy for immune cell activation and killing of tumor cells through antibody-dependent cellular cytotoxicity (ADCC). Among these, tetravalent, bispecific innate cell engagers (ICE®) with specificity for the activating receptor CD16A selectively triggering innate responses from NK cells or macrophages represent the most clinically advanced concept. The CD30/CD16A specific ICE® AFM13, has shown efficacy in patients with CD30+ lymphomas as monotherapy1 and combination therapy with check-point inhibitors2 and most recently in combination with adoptive NK cell therapy.3 The EGFR/CD16A specific ICE® AFM24, targeting a variety of solid tumors like colorectal, or lung cancer with a unique mode of action independent of EGFR signaling inhibition, is currently evaluated in an ongoing Ph1/2a clinical study.MethodsWe used a microchip-based screening with single cell resolution4 to elucidate the dynamic responses of individual NK cells towards tumor target cells upon treatment with AFM13 or AFM24.ResultsWe found that AFM13 and AFM24 mediated potent activation of NK cells, leading to increased responsive cytotoxic NK cells and significantly increased the number of NK cells that exerted engagement with multiple target cells rendering these NK cells serial killers. Strikingly, bispecific ICE® molecules triggered stronger cytotoxic responses compared to monoclonal antibodies. One suggested strategy to boost killing by NK cells is to use molecular inhibitors or protein constructs that prevent shedding of CD16.5 However, previous results have shown that this can lead to impaired detachment from target cells, reducing the capacity for an individual NK cell to form serial contacts to target cells.6 We observed that the elevated NK cell killing induced by ICE® molecules was largely conserved when cells were treated with the shedding inhibitor Batimastat. Analysis of the functional dynamics of NK cells revealed that inhibition of CD16 shedding prevented NK cell detachment from target cells, resulting in cell cluster formation. This might strongly impact targeting of distant tumor cells by an individual NK cell thus limiting its anti-tumoral activity.ConclusionsIn conclusion, we show that both AFM13 and AFM24 increase the fraction of tumor-target responsive NK cells and boost serial killing of target cells by individual NK cells. Based on these data, ICE® molecules can be characterized as potent anti-tumoral agents leveraging the enormous potential of NK cells while maintaining crucial features of NK cell biology.AcknowledgementsWe thank members of the Önfelt lab for their valuable help and feedback.ReferencesSawas A, Elgedawe H, Vlad G, Lipschitz M, Chen P-H, Rodig SJ, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood 2018;132(Supplement 1):2908–2908.Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, Garcia-Sanz R, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020. Blood 2020;136(21):2401–2409.Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood–derived NK cells facilitates CAR-like responses against CD30 + malignancies. Clin Cancer Res Epub 2021.Guldevall K, Brandt L, Forslund E, Olofsson K, Frisk TW, Olofsson PE, et al. Microchip screening platform for single cell assessment of NK cell cytotoxicity. Front Immunol 2016;7:119.Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013;121(18):3599–608.Srpan K, Ambrose A, Karampatzakis A, Saeed M, Cartwright ANR, Guldevall K, et al. Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells. J Cell Biol 2018;217(9):3267–83.Ethics ApprovalThis work was performed with NK cells from healthy anonymous blood donors, which requires no ethical permit according to local regulations.

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