Serine protease inhibitors interact with IFN-γ through up-regulation of FasR; a novel therapeutic strategy against cancer

Shadrin, Natalia; Shapira, Michal; Khalfin, Boris; Uppalapati, Lakshminarasaiah; Parola, Abraham H.; Nathan, Ilana

doi:10.1016/j.yexcr.2014.11.005

Cited by 12 publications

(6 citation statements)

References 26 publications

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“…In the case of BiTE ® -induced bystander killing, FAS and ICAM-1 were both upregulated on the antigen-negative cells, which helped contribute to the bystander killing process that took place over a matter of hours after initial contact of the BiTE ® with the antigen-positive tumor cells [381]. It is known that IFN- γ can upregulate Fas (CD95) on the surface of cancer cells [382]. Since both CAR-T cells [380] and TRBA-induced T-cell killers [381] both induce the production of IFN- γ as part of their activation and killing process, it is likely that Fas-mediated apoptosis of bystander cells may be more prevalent than shown in just these few studies.…”

Section: Targets For Clinical Stage Trbas and Car-t Cellsmentioning

confidence: 99%

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

2019

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The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory agencies within the last ten years for the treatment of hematological cancers and an additional 53 TRBAs and 246 CAR cell constructs are in clinical trials today. Two major groups of TRBAs include small, short-half-life bispecific antibodies that include bispecific T-cell engagers (BiTE®s) which require continuous dosing and larger, mostly IgG-like bispecific antibodies with extended pharmacokinetics that can be dosed infrequently. Most CAR-T cells today are autologous, although significant strides are being made to develop off-the-shelf, allogeneic CAR-based products. CAR-Ts form a cytolytic synapse with target cells that is very different from the classical immune synapse both physically and mechanistically, whereas the TRBA-induced synapse is similar to the classic immune synapse. Both TRBAs and CAR-T cells are highly efficacious in clinical trials but both also present safety concerns, particularly with cytokine release syndrome and neurotoxicity. New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment.

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Section: Targets For Clinical Stage Trbas and Car-t Cellsmentioning

confidence: 99%

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

2019

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“…Understanding the changing nature of susceptibility to immune-modulated killing mechanisms due to oncogene expression holds the key to optimizing immunotherapy for HPV-related cancers. Using a protease inhibitor to sensitize tumors to apoptosis resulted in enhanced IFNγ production, increased Fas expression and improved tumor lysis in vivo [ 42 ]. Likewise, inhibition of PD1/L1 reduces T cell death and improves eradication of HPV-related tumors in immunomodulatory therapy [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus E7 oncoprotein expression by keratinocytes alters the cytotoxic mechanisms used by CD8 T cells

et al. 2017

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Cervical cancer is a malignant transformation of keratinocytes initiated by the E7 oncoprotein of human papillomavirus (HPV). These tumors are characterized by keratinocyte hyperproliferation and are often infiltrated with activated CD8 T cells. HPV infection confers changes to gain immunological advantage to promote chronic infection, and these persist with malignant transformation. We investigated the relative importance of the many redundant mechanisms of cytotoxicity used by CD8 T cells to kill keratinocytes expressing HPV E7 oncoprotein using extended-duration time-lapse microscopy that allows examination of cell-to-cell interactions during killing. E7 expression by keratinocytes increased susceptibility to cell-mediated killing. However, while killing of non-transgenic keratinocytes was traditional, perforin-mediated, and caspase-dependent, E7-expression favored killing by perforin-independent, caspase-independent mechanisms. The roles of perforin, TNFα, IFNγ, Fas/FasL and PD1/PD-L1 were graded according to target cell survival to produce a hierarchy of killing mechanisms utilized in killing E7-expressing cells. TNFα was essential for perforin-mediated killing of E7-expressing cells, but not perforin-independent killing. IFNγ facilitated killing by Fas/FasL interaction, especially in the absence of perforin. Additionally, expression of E7 offered protection from killing by up regulation of PD-L1, Fas and FasL expression on keratinocytes promoting fight-back by target cells, resulting in effector cell death. This study shows that keratinocytes expressing E7 are highly susceptible to killing by CD8 T cells, but utilizing different armamentarium. Down-regulation of CD8 T cell cytotoxicity in HPV-related tumors may be due to suppression by E7-expressing keratinocytes. Immunotherapy for HPV-related cancers may be improved by suppression of PD-L1, or by suppression of FasL.

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“…Protease inhibitors occur naturally in living organisms, including animals (Shadrin et al, 2015; Vicuna et al, 2015; Wang et al, 2005; Zhang, 2006), plants (Kim et al, 2009; Ryan, 1990), fungi (Sabotic & Kos, 2012), and bacteria (Supuran et al, 2002). They have multifunctional roles in many physiological processes and play an important role in biological functions of venomous animals, such as in predation (Birrell et al, 2007) and defense (Ali et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Purification and characterization of a novel anti-coagulant from the leech Hirudinaria manillensis

Cheng¹,

Tang²,

Long³

et al. 2019

Zoological Research

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Protease inhibitors have been reported rarely from the leech Hirudinaria manillensis . In this study, we purified a novel protease inhibitor (bdellin-HM-2) with anticoagulant properties from H. manillensis . With a molecular weight of 1.4x10 4 , bdellin-HM-2 was also characterized with three intra-molecular disulfide bridges at the N-terminus and multiple HHXDD and HXDD motifs at the C-terminus. cDNA cloning revealed that the putative nucleotide-encoding protein of bdellin-HM-2 contained 132 amino acids and was encoded by a 399 bp open reading frame (ORF). Sequence alignment showed that bdellin-HM-2 shared similarity with the “non-classical” Kazal-type serine protease inhibitors, but had no inhibitory effect on trypsin, elastase, chymotrypsin, kallikrein, factor XIIa (FXIIa), factor XIa (FXIa), factor Xa (FXa), thrombin, or plasmin. Bdellin-HM-2 showed anticoagulant effects by prolonging the activated partial thromboplastin time (aPTT), indicating a role in enabling H. manillensis to obtain a blood meal from its host. Our results suggest that bdellin-HM-2 may play a crucial role in blood-sucking in this leech species and may be a potential candidate for the development of clinical anti-thrombotic drugs.

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Serine protease inhibitors interact with IFN-γ through up-regulation of FasR; a novel therapeutic strategy against cancer

Cited by 12 publications

References 26 publications

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

Human papillomavirus E7 oncoprotein expression by keratinocytes alters the cytotoxic mechanisms used by CD8 T cells

Purification and characterization of a novel anti-coagulant from the leech Hirudinaria manillensis

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