Cytotoxicity of CD8+ T lymphocytes for tumor cells as determined in vitro is not always the basis of tumor rejection in vivo

1995 ◽  
Vol 121 (S1) ◽  
pp. A8-A8
Author(s):  
O. Utermöhlen ◽  
J. Zerrahn ◽  
F. Lehmann-Grube ◽  
W. Deppert
Keyword(s):  
T Lymphocytes ◽  
Tumor Cells ◽  
Tumor Rejection ◽  
Cd8 T Lymphocytes

scholarly journals IFN-γ down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Guoping Ding ◽  
Tao Shen ◽  
Chen Yan ◽  
Mingjie Zhang ◽  
Zhengrong Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cd8 T Lymphocytes ◽  
Ifn Γ

Abstract Background Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer. Methods Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-γ, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured. Results PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-γ could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-γ resulted in greatest effect of PD-1-blockde (1.73 ± 0.78), compared with IFN-γ along (18.63 ± 0.82) and nivolumab along (13.65 ± 1.22). Moreover, the effects of nivolumab plus IFN-γ largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-γ presented the best repression of tumor growth. Conclusions IFN-γ plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.

Antitumor activity against established intracerebral gliomas exhibited by cytotoxic T lymphocytes, but not by lymphokine-activated killer cells

1992 ◽  
Vol 77 (5) ◽  
pp. 757-762 ◽  
Author(s):  
Frank P. Holladay ◽  
Teresa Heitz ◽  
Gary W. Wood
Keyword(s):  
Brain Tumor ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Lak Cells ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells ◽  
Brain Tumor Cells

✓ Specific immune responses against malignant brain tumors have been difficult to demonstrate. Moreover, immunotherapy has met with little success, despite using lymphocytes with high levels of cytotoxicity against brain tumor cells. Lymphokine-activated killer (LAK) cells that nonspecifically kill brain tumor cells are produced by stimulating resting precursors with high concentrations of interleukin-2 (IL-2). Cytotoxic T lymphocytes that specifically kill brain tumor cells are produced by stimulating antigen receptor-positive immune-cell precursors with tumor cells. In an attempt to gain insight into immune cell function against brain tumors, the present study compared the in vitro and in vivo activities of LAK cells and cytotoxic T lymphocytes produced against RT2, a fast-growing rat glioma cell line. Lymphokine-activated killer cells were produced by stimulating normal rat spleen cells with 1000 units of IL-2, and RT2-specifie cytotoxic T lymphocytes were produced by priming them in vivo with RT2 and Corynebacterium parvum and restimulating primed spleen cells with RT2 in vitro. Lymphokine-activated killer cells were highly cytotoxic for a panel of syngeneic and allogeneic brain tumor and non-brain tumor target cells, including RT2, as measured in a 4-hour 51Cr release assay. Cytotoxic T lymphocytes were highly cytotoxic only for syngeneic brain tumor target cells. Lymphokine-activated killer cells and cytotoxic T lymphocytes were tested for in vivo antitumor activity against intracerebral RT2 by intravenous adoptive transfer of activated lymphocytes. Untreated rats died in approximately 2 weeks. Lymphokine-activated killer cells plus IL-2 failed to affect survival when treatment was initiated as early as 1 day following tumor inoculation. Cytotoxic T lymphocytes and IL-2 administered as late as Day 5 rejected progressing intracerebral tumor. Thus, although both cytotoxic T lymphocytes and LAK cells exhibited high levels of in vitro killing of glioma cells, only cytotoxic T lymphocytes rejected progressing intracerebral tumors.

scholarly journals The Cardioprotective Protein Apolipoprotein A1 Promotes Potent Anti-tumorigenic Effects

2013 ◽  
Vol 288 (29) ◽  
pp. 21237-21252 ◽  
Author(s):  
Maryam Zamanian-Daryoush ◽  
Daniel Lindner ◽  
Thomas C. Tallant ◽  
Zeneng Wang ◽  
Jennifer Buffa ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Density Lipoprotein ◽  
Tumor Formation ◽  
Tumor Rejection ◽  
Apolipoprotein A1 ◽  
Major Protein ◽  
Tumor Growth And Metastasis

Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b+ F4/80+ macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.

scholarly journals B7H Costimulates Clonal Expansion of, and Cognate Destruction of Tumor Cells by, CD8+ T Lymphocytes In Vivo

2001 ◽  
Vol 194 (9) ◽  
pp. 1339-1348 ◽  
Author(s):  
Xingluo Liu ◽  
Xue-Feng Bai ◽  
Jing Wen ◽  
Jian-Xin Gao ◽  
Jinqing Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Tumor Antigen ◽  
Costimulatory Molecule ◽  
Clonal Expansion ◽  
Immune Protection ◽  
Large Tumor ◽  
Cd8 T Lymphocytes

B7H/B7RP (hereby called B7H) is a new member of the B7 family of costimulatory molecules and interacts with inducible costimulatory molecule (ICOS). Its function for CD8 T cells has not been reported. We report here that expression of B7H on the tumor cells reduced tumorigenicity and induced immunity to subsequent challenge with parental tumor cells. The immune protection correlates with an enhanced cytotoxic T lymphocyte (CTL) response against P1A, the major tumor antigen expressed in the J558 tumor. To understand the mechanism of immune protection, we adoptively transferred transgenic T cells specific for tumor antigen P1A into mice that bore P1A-expressing tumors. We found that while the transgenic T cells divided faster in mice bearing the B7H+ tumors, optimal B7H-induced clonal expansion of P1CTL required costimulation by B7–1 and B7–2 on the endogenous host antigen-presenting cells (APCs). Interestingly, when B7H+ and B7H− tumors were coinjected, P1CTL selectively eliminated the B7H+ tumor cells. Moreover, B7H expressed on the tumor cells made them highly susceptible to destruction by CTL in vivo, even if the CTL was administrated into mice with large tumor burdens. Tumors that recurred in the P1CTL-treated mice lost transfected B7H and/or H-2Ld, the class I molecule that presents the P1A peptide. Taken together, our results reveal that B7H costimulates clonal expansion of, and cognate destruction by CD8+ T lymphocytes in vivo.

scholarly journals Isolation of antigen-specific CD8+ T lymphocytes in vitro and in vivo

2013 ◽  
Vol 1 (S1) ◽  
Author(s):  
Carina Wehner ◽  
Christian Ellinger ◽  
Silke Raffegerst ◽  
Susanne Wilde ◽  
Barbara Mosetter ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cd8 T Lymphocytes

scholarly journals IMMUNOLOGIC REJECTION OF DIETHYLNITROSAMINE-INDUCED HEPATOMAS IN STRAIN 2 GUINEA PIGS

1973 ◽  
Vol 137 (3) ◽  
pp. 751-775 ◽  
Author(s):  
Harold F. Dvorak ◽  
Ann M. Dvorak ◽  
Winthrop H. Churchill
Keyword(s):  
Tumor Cells ◽  
Guinea Pigs ◽  
Inflammatory Infiltrate ◽  
Light And Electron Microscopy ◽  
Inflammatory Cells ◽  
Tumor Rejection ◽  
Tumor Resistance ◽  
Skin Reactions

The morphologic events associated with the immunologic rejection by strain 2 guinea pigs of ascites variants of two lines of diethylnitrosamine-induced tumors have been studied by light and electron microscopy. Tumor injection sites in the skin of control animals exhibited clusters of viable, actively mitotic tumor cells along with a modest inflammatory infiltrate composed of lymphocytes, macrophages, neutrophils, and rare basophils. In contrast, similar injections of either tumor line in specifically sensitized guinea pigs elicited typical delayed-type skin reactions associated with tumor cell necrosis and a more extensive inflammatory infiltrate including a selective increase in the number of basophilic leukocytes (12%, line 1, or 23%, line 10, of total inflammatory cells). That basophils may have a role in tumor resistance in vivo is suggested by the close anatomic associations observed between basophils and tumor cells, and by the fact that basophils were the only inflammatory cell to demonstrate a relative increase in frequency in the lesions of sensitized as compared with control animals. Moreover, intraperitoneal injection of line 1 tumor in specifically sensitized animals elicited a striking basophilia within 24 h. Unlike macrophages, basophils did not phagocytose tumor cells but did evidence occasional extrusion of granules and frequently exhibited loss of granule staining density, a change that may be related to release of mediator substances. Electron microscope studies of line 1 tumor rejection in the peritoneal cavities of specifically sensitized guinea pigs demonstrated aggregations of "activated" macrophages, lymphocytes, basophils, and damaged or dead tumor cells. These aggregates, held together by complex interdigitations of macrophage villi, closely resembled those occurring in vitro among peritoneal exudate cells whose migration from capillary tubes was inhibited by migration inhibition factor (MIF). Moreover, cells in these aggregates, as well as macrophages inhibited by MIF in vitro, lacked a normal coating of cell surface material.

In SilicoDesigning a Novel Multi-epitope DNA Vaccine against Anti-apoptotic Proteins in Tumor Cells

2019 ◽  
Vol 16 (3) ◽  
pp. 222-230
Author(s):  
Shirin Mahmoodi ◽  
Navid Nezafat
Keyword(s):  
T Lymphocytes ◽  
Tumor Cells ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Physicochemical Characteristics ◽  
Apoptotic Proteins ◽  
Immunological Assays ◽  
Cancer Immunotherapeutic

Background:Cancer therapy has been known as one of the most important challenges in the world. Various therapeutic methods such as cancer immunotherapy are used to eradicate tumor cells. Vaccines have an important role among different cancer immunotherapeutic approaches. In the field of vaccine production, bioinformatics approach is considered as a useful tool to design multi-epitope cancer vaccines, mainly for selecting immunodominant Cytotoxic T Lymphocytes (CTL) and Helper T Lymphocytes (HTL) epitopes.Objective:Generally, to design efficient multi-epitope cancer vaccines, Tumor-Specific Antigens (TSA) are targeted. In the context of DNA-based cancer vaccines, they contain genes that code tumor antigens and are delivered to host by different methods.Methods:In this study, the anti-apoptotic proteins (BCL2, BCL-X, survivin) that are over-expressed in different tumor cells were selected for CTL and HTL epitopes prediction through different servers such as RANKPEP, CTLpred, and BCPREDS.Results:Three regions from BCL2 and one region from BCL-X were selected as CTL epitopes and two segments from survivin were defined as HTL epitopes. In addition, β-defensin was used as a proper adjuvant to enhance vaccine efficacy. The aforesaid segments were joined together by appropriate linkers, and some important properties of designed vaccine such as antigenicity, allergenicity and physicochemical characteristics were determined by various bioinformatics servers.Conclusion:Based on the bioinformatics results, the physicochemical and immunological features showed that the designed vaccine construct can be used as an efficient cancer vaccine after its efficacy was confirmed by in vitro and in vivo immunological assays.

In Vivo and in Vitro Suppression of T-Cell Receptor α/β CD4-CD8- T Lymphocytes by Cyclosporine A

1993 ◽  
Vol 67 (3) ◽  
pp. 224-231 ◽  
Author(s):  
Edward G. Brooks ◽  
Daniel P. Wirt ◽  
Gary R. Klimpel ◽  
Smita Vaidya ◽  
Randall M. Goldblum
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cyclosporine A ◽  
Cell Receptor ◽  
Cd8 T Lymphocytes
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