scholarly journals Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma

2008 ◽  
Vol 205 (9) ◽  
pp. 2125-2138 ◽  
Author(s):  
Sergio A. Quezada ◽  
Karl S. Peggs ◽  
Tyler R. Simpson ◽  
Yuelei Shen ◽  
Dan R. Littman ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Clinical Results ◽  
Tumor Rejection ◽  
Cell Depletion ◽  
Effector Cells ◽  
T Effector Cells ◽  
Melanoma Model

Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte–associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4+CD25+ T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment. Failure to promote rejection with therapeutic depletion is not related to lack of T reg cell depletion, to elimination of CD25+ effector T cells, or to a failure to enhance systemic antitumor T cell responses, but correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell. Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy. The data demonstrate a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggest an alternative, clinically applicable strategy for the treatment of established tumors.

scholarly journals Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

2021 ◽  
Vol 22 (8) ◽  
pp. 4109
Author(s):  
Mankgopo M. Kgatle ◽  
Tebatso M. G. Boshomane ◽  
Ismaheel O. Lawal ◽  
Kgomotso M. G. Mokoala ◽  
Neo P. Mokgoro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cancer Control ◽  
Lymphocyte Activation ◽  
Immune Checkpoints ◽  
Mortality And Morbidity ◽  
Domain 3

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct

2005 ◽  
Vol 55 (5) ◽  
pp. 503-514 ◽  
Author(s):  
Bernd Schlereth ◽  
Cornelia Quadt ◽  
Torsten Dreier ◽  
Peter Kufer ◽  
Grit Lorenczewski ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Single Chain ◽  
Single Chain Antibody

scholarly journals 566 ATOR-1017, a second generation 4–1BB antibody with potential to enhance efficacy of PD-1 therapies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A595-A595
Author(s):  
Karin Enell Smith ◽  
Anneli Nilsson ◽  
Peter Ellmark
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Effector Cells ◽  
Costimulatory Receptor ◽  
T Effector Cells ◽  
Murine Colon Carcinoma ◽  
Activation Profile

BackgroundATOR-1017 is a Fcγ-receptor (FcγR) crosslinking dependent agonistic IgG4 antibody targeting the costimulatory receptor 4 1BB, designed for improved tolerability and efficacy. 4-1BB is highly expressed on tumor infiltrating CD8+ T effector cells (T effs) in several cancer indications. By binding to 4-1BB, ATOR-1017 enhances the activity of tumor reactive T effs and NK cells within the tumor and induces a potent anti-tumor response. 4-1BB is a promising candidate for immunotherapy and holds great potential for combination with other immunomodulatory antibodies, targeting e.g. the PD-1 pathway.MethodsHuman 4-1BB knock-in transgenic mice with established murine colon carcinoma MC38 tumors were used to demonstrate anti-tumor efficacy after systemic treatment with ATOR-1017 in combination with anti-PD-1. Further, the effect of combining ATOR-1017 with anti-PD-1 on T cell activation (measured as production of IFNγ) was evaluated in a mixed lymphocyte reaction (MLR) assay with human primary CD4+ T cells and mature monocyte-derived DCs (mDC) expressing endogenous levels of both 4-1BB and PD-1.ResultsATOR-1017 in combination with anti-PD-1 improved survival and reduced tumor growth signifcantly in human 4-1BB knock-in transgenic mice with established tumors compared with each monotherapy alone. The potential for combining ATOR-1017 and PD-1 was further supported by data from a MLR assay demonstrating that the combination of ATOR-1017 with anti-PD-1 induced a more potent CD4+ T cells activation than each monotherapy alone.The functional activation profile of ATOR-1017 is expected to minimize the risk of systemic immune activation and toxicity, by directing a potent immune response to immune cells in tumor tissue and tumor draining lymph nodes. This is supported by early data from the ongoing first-in-human phase I study where ATOR-1017 has been shown to be safe and tolerable.ConclusionsIn summary, these results support further clinical development of ATOR-1017 in combination with PD-1 antibodies. By combining ATOR-1017 with anti-PD-1, tumor infiltrating T cells can be more effectively activated and potentially increase the response rate in multiple indications.Ethics ApprovalAll animal procedures were in accordance to IACUC guidance

scholarly journals Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001521
Author(s):  
Javier Arranz-Nicolás ◽  
Miguel Martin-Salgado ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Maria C Moreno-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Tumor Rejection ◽  
Cytotoxic T Cell ◽  
Adenocarcinoma Cells ◽  
The Impact

BackgroundThe inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.MethodsWe used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

scholarly journals Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency

2019 ◽  
Vol 40 (2) ◽  
pp. 277-288 ◽  
Author(s):  
Hassan Abolhassani ◽  
Yasser M. El-Sherbiny ◽  
Gururaj Arumugakani ◽  
Clive Carter ◽  
Stephen Richards ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Clinical Phenotype ◽  
Compound Heterozygous ◽  
Dominant Phenotype ◽  
Cytokine Responses ◽  
Whole Exome ◽  
Stimulation Of

Abstract Background Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

Autoaggression and tumor rejection: it takes more than self-specific T-cell activation

1999 ◽  
Vol 169 (1) ◽  
pp. 263-272 ◽  
Author(s):  
Ruth Ganss ◽  
Andreas Limmer ◽  
Torsten Sacher ◽  
Bernd Arnold ◽  
Gunter J. Hammerling
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Rejection

scholarly journals Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Blockade Accelerates the Acute Rejection of Cardiac Allografts in CD28-deficient Mice: CTLA4 Can Function Independently of CD28

1998 ◽  
Vol 188 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Hua Lin ◽  
Jeffrey C. Rathmell ◽  
Gary S. Gray ◽  
Craig B. Thompson ◽  
Jeffrey M. Leiden ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Graft Rejection ◽  
Allograft Rejection ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Wild Type ◽  
Lymphocyte Antigen ◽  
Deficient Mice

Cytotoxic T lymphocyte antigen 4 (CTLA4) appears to negatively regulate T cell activation. One mechanism by which CTLA4 might antagonize T cell function is through inhibition of CD28 signaling by competing for their shared ligands B7-1 and B7-2. In addition, CTLA4 ligation could initiate a signaling cascade that inhibits T cell activation. To address whether CTLA4 could inhibit immune responses in the absence of CD28, rejection of heart allografts was studied in CD28-deficient mice. H-2q hearts were transplanted into allogeneic wild-type or CD28-deficient mice (H-2b). Graft rejection was delayed in CD28-deficient compared with wild-type mice. Treatment of wild-type recipients with CTLA4-immunoglobulin (Ig), or with anti–B7-1 plus anti–B7-2 mAbs significantly prolonged allograft survival. In contrast, treatment of CD28-deficient mice with CTLA4-Ig, anti–B7-1 plus anti–B7-2 mAbs, or a blocking anti-CTLA4 mAb induced acceleration of allograft rejection. This increased rate of graft rejection was associated with more severe mononuclear cell infiltration and enhanced levels of IFN-γ and IL-6 transcripts in donor hearts of untreated wild-type and CTLA4-Ig– or anti-CTLA4 mAb–treated CD28-deficient mice. Thus, the negative regulatory role of CTLA4 extends beyond its potential ability to prevent CD28 activation through ligand competition. Even in the absence of CD28, CTLA4 plays an inhibitory role in the regulation of allograft rejection.

scholarly journals Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+Regulatory T Cells

2012 ◽  
Vol 287 (14) ◽  
pp. 11098-11107 ◽  
Author(s):  
Jozsef Karman ◽  
Ji-Lei Jiang ◽  
Nathan Gumlaw ◽  
Hongmei Zhao ◽  
Juanita Campos-Rivera ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocyte Antigen
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