Molecular mechanisms of T cell co-stimulation and co-inhibition

Chen, Lieping; Flies, Dallas B.

doi:10.1038/nri3405

Cited by 2,465 publications

(2,396 citation statements)

References 133 publications

Supporting

Mentioning

2,257

Contrasting

Unclassified

Order By: Relevance

“…33 This requires upregulation of peptide-presenting MHC class II and class I molecules as well as enhanced expression of co-stimulatory signals, including CD80, CD86, and CD40, which are necessary for proper T cell activation via CD28 and CD40L. 34 Along these lines, it becomes increasingly evident that monocytic cells can give rise to a population of monocytic APCs which are of importance for the stimulation of anti-tumor immune mechanisms during cancer therapy – at least in mouse tumor models. 8,35,36 For anthracycline-based chemotherapy, it has already been shown that dying cancer cells can stimulate the differentiation of recruited monocytes into antigen-presenting DCs.…”

Section: Resultsmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

View full text Add to dashboard Cite

The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 × 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses – at least in models of triple-negative breast cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Therefore, PBMCs were stained with carboxyfluorescein diacetate succinimidyl ester (CFSE) at 625 nM per 1 × 10 5 cells/mL according to the manufacturer’s instructions and 1.5x10 4 PBMCs per well were incubated with 30 nM scDuokines. Depending on the setting, T cells were activated with donor-specific suboptimal concentrations (3–11 ng/mL) of cross-linked anti-human CD3 antibody.…”

Section: Methodsmentioning

confidence: 99%

“…B16-FAP cells (1x10 5 in 150 µL PBS) were injected intravenously into female C57BL/6NCrl mice (6 mice per group). As treatment, mice received six intraperitoneal injections of 200 pmol murine scDuokine (msc4-1BBL-mscCD40L or msc4-1BBL-mscCD27L) in combination with 4 pmol bispecific antibody (scDb332C11) on days 1, 2, 3 and days 8, 9, 10 after tumor cell engraftment.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

View full text Add to dashboard Cite

Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

show abstract

“…DCs express several costimulatory signaling molecules on their surface, such as CD80/86 (B7‐1/2), CD40, ICOSL, and OX40L that bind to costimulatory receptors, such as CD28, CD40L, ICOS, OX40, and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) on the surface of T cells 28. This binding results in full activation of T cells (effector T cells (Teff)), which in turn leads to the production of interleukin (IL)‐2 and other cytokines, whereas the absence of a secondary signal leads to T cell anergy 29, 30. The kinetics of the signal mediated by the costimulatory molecules depends on their expression dynamics—some molecules, such as CD80/86 and CD28, are expressed at the early stage of activation, whereas others, such as CTLA‐4, are expressed at the late stage.…”

Section: Immune System and Its Complexitymentioning

confidence: 99%

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

Rahman

Tiwari

Narula

et al. 2018

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

The human adaptive immune system is a very complex network of different types of cells, cytokines, and signaling molecules. This complex network makes it difficult to understand the system level regulations. To properly explain the immune system, it is necessary to explicitly investigate the presence of different feedback and feedforward loops (FFLs) and their crosstalks. Considering that these loops increase the complexity of the system, the mathematical modeling has been proved to be an important tool to explain such complex biological systems. This review focuses on these regulatory loops and discusses their importance on systems modeling of the immune system.

show abstract

Molecular mechanisms of T cell co-stimulation and co-inhibition

Cited by 2,465 publications

References 133 publications

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

Contact Info

Product

Resources

About