scholarly journals Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)

2019 ◽  
Vol 129 (9) ◽  
pp. 3594-3609 ◽  
Author(s):  
Nune Markosyan ◽  
Jinyang Li ◽  
Yu H. Sun ◽  
Lee P. Richman ◽  
Jeffrey H. Lin ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Antitumor Immunity ◽  
Cox 2

Intratumoral CD8+ Lymphocyte Infiltration as a Prognostic Factor and Its Relationship With Cyclooxygenase 2 Expression and Microsatellite Instability in Endometrial Cancer

2015 ◽  
Vol 25 (7) ◽  
pp. 1165-1172 ◽  
Author(s):  
Tomohiro Suemori ◽  
Nobuyuki Susumu ◽  
Takashi Iwata ◽  
Kouji Banno ◽  
Wataru Yamagami ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Antitumor Immunity ◽  
Proportional Hazards ◽  
Cyclooxygenase 2 ◽  
Repair System ◽  
Fisher Exact Probability Test ◽  
Exact Probability ◽  
Dna Mismatch Repair System ◽  
Cox 2

ObjectiveMicrosatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer.MethodsThe data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8+T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses.ResultsThe MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2–high group showed significantly fewer TILs than did the COX-2–low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression.ConclusionsThe number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

Effect of tumor cell-derived debris and IgG on metastasis of pancreatic cancer and inflammation through tumor-associated macrophages.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15764-e15764
Author(s):  
Qi Zhang ◽  
Qi Chen ◽  
Xueli Bai ◽  
Jianxin Wang ◽  
Tingbo Liang
Keyword(s):  
Tumor Cell ◽  
Epithelial Mesenchymal Transition ◽  
Hepatoma Cell ◽  
Ductal Adenocarcinoma ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Mesenchymal Transition ◽  
Cox 2 ◽  
Anti Inflammatory

e15764 Background: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumor microenvironment. Most tumor-associated macrophages (TAMs) are M2 phenotypic macrophages, which normally show anti-inflammatory functions in numerous disorders. We previously found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation of hepatoma cell-derived debris, but the molecular mechanism was unclear. Methods: Macrophages were induced using tumor cell debris. Xenograft mouse model was established. Immunoblotting and immunochemistry were used to test protein expression. Results: The M2 macrophages-derived inflammation also existed in PDAC. We proved that the necrotic debris of PDAC cells induced potent IL-1β release by M2 macrophages via TLR4/TRIF/NF-κB signaling, and this effect was further boosted by IgG that also derived from PDAC cells. We further revealed that increased IL-1β promoted epithelial-mesenchymal transition (EMT) and consequent metastasis of PDAC cells. Using a selective COX-2 inhibitor celecoxib, we enhanced the anti-tumoral efficacy of gemcitabine. Conclusions: These data revealed a special pro-inflammatory phenomenon and mechanism in PDAC, and indicated that IL-1β and COX-2 can be therapeutic targets of anti-inflammatory strategy in PDAC treatment.

scholarly journals T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

2021 ◽  
Vol 14 (11) ◽  
pp. 1172
Author(s):  
Daisuke Kamakura ◽  
Ryutaro Asano ◽  
Masahiro Yasunaga
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Bispecific Antibodies ◽  
Tumor Site ◽  
Tumor Cell Death

As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

scholarly journals Subversion of host defense mechanisms by murine tumors. II. Counter-influence of concomitant antitumor immunity.

1976 ◽  
Vol 143 (3) ◽  
pp. 574-584 ◽  
Author(s):  
R J North ◽  
D P Kirstein ◽  
R L Tuttle
Keyword(s):  
Tumor Cell ◽  
Host Defense ◽  
Primary Tumor ◽  
Defense Mechanisms ◽  
Antitumor Immunity ◽  
Malignant Tumors ◽  
Acquired Resistance ◽  
Antibacterial Resistance ◽  
Stages Of Growth ◽  
Murine Tumor Cells

Subcutaneous injection of murine tumor cells first resulted in a state of severely suppressed macrophage-mediated antibacterial resistance and then in a contrasting state of greatly enhanced antibacterial resistance. Whereas, the state of suppressed antibacterial resistance corresponded to a state of suppressed resistance to a tumor cell challenge, the generation of enhanced antibacterial resistance corresponded to the acquisition of concomitant antitumor immunity. It was suggested on the basis of this evidence that changes in the level of macrophage-mediated antibacterial resistance that occur during growth of the primary tumor reflected changes in the level of the host's resistance to the tumor itself. It was further suggested that the coincidental suppression of antibacterial and antitumor resistance that occurs during the initial stages of growth of the primary tumor represents the operation of a mechanism that enables the tumor to avoid destruction by macrophages. The results support the view that macrophages play an important role in native and acquired resistance to malignant tumors.

Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2526-2534 ◽  
Author(s):  
Peter Ruf ◽  
Horst Lindhofer
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Residual Disease ◽  
B Cell Lymphoma ◽  
Disseminated Tumor Cells ◽  
Cell Killing ◽  
Tumor Cell Killing

Abstract Bispecific antibodies (bsAbs) can efficiently mediate tumor cell killing by redirecting preactivated or costimulated T cells to disseminated tumor cells, especially in a minimal residual disease situation. This study demonstrates that the trifunctional bsAb BiLu is able to kill tumor cells very efficiently without any additional costimulation of effector cells in vitro and in vivo. Remarkably, this bsAb also induces a long-lasting protective immunity against the targeted syngeneic mouse tumors (B16 melanoma and A20 B-cell lymphoma, respectively). A strong correlation was observed between the induction of a humoral immune response with tumor-reactive antibodies and the survival of mice. This humoral response was at least in part tumor specific as shown in the A20 model by the detection of induced anti-idiotype antibodies. Both the survival of mice and antitumor titers were significantly diminished when F(ab′)2 fragments of the same bsAb were applied, demonstrating the importance of the Fc region in this process. With the use of T-cell depletion, a contribution of a cellular antitumor response could be demonstrated. These results reveal the necessity of the Fc region of the bsAb with its potent immunoglobulin subclass combination mouse immunoglobulin G2a (IgG2a) and rat IgG2b. The antigen-presenting system seems to be crucial for achieving an efficient tumor cell killing and induction of long-lasting antitumor immunity. Hereby, the recruitment and activation of accessory cells by the intact bsAb is essential.

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