Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States

Wei, SC; Sharma, R; Anang, NAS; Levine, JH; Zhao, Y; Mancuso, JJ; Setty, M; Sharma, P; Wang, J; Pe'er, D; Allison, JP

doi:10.21417/sw2019ci

Cited by 5 publications

(5 citation statements)

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“…In 2019, several studies have shown that the two most prominent checkpoint inhibitors, anti-CTLA4 and anti-PD-1/PD-L1 convey distinctly different effects: CTLA-4 inhibition relieves constraints on CD4+ T cell phenotypes and allows for the differentiation of inducible costimulator (ICOS)+ CD4 Th1 cells [ 162 ], while anti-PD-1/PD-L1 therapy predominantly influences CD8+ lymphocytes and induces a TCF7-mediated increase of memory precursor-like CD8+ T cells [ 163 ]. It has furthermore been demonstrated that an efficient checkpoint inhibitor-induced antitumor response requires the expression of MHC class II-restricted antigens by tumor cells, combined with a local activation of CD4+ T cells to recruit and activate CD8+ T cells [ 164 , 165 ].…”

Section: Immunological Therapeutic Approachesmentioning

confidence: 99%

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Lurje

Hammerich

Tacke

2020

IJMS

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Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.

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Section: Immunological Therapeutic Approachesmentioning

confidence: 99%

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Lurje

Hammerich

Tacke

2020

IJMS

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“…In contrast to CTLA‐4, the PD‐1 pathway appears to control the ongoing activity of CD4 and CD8 T cells following immune activation (Wei et al , 2017, 2019). Like CTLA‐4, PD‐1 also binds to two ligands (PD‐L1 and PD‐L2), which whilst expressed on APCs also have a much wider tissue distribution (Schildberg et al , 2016).…”

Section: Introductionmentioning

confidence: 99%

The CTLA‐4 immune checkpoint protein regulates PD‐L1:PD‐1 interaction via transendocytosis of its ligand CD80

Kennedy¹,

Robinson²,

Hinze³

et al. 2023

The EMBO Journal

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CTLA-4 and PD-1 are key immune checkpoint receptors that are targeted in the treatment of cancer. A recently identified physical interaction between the respective ligands, CD80 and PD-L1, has been shown to block PD-L1/PD-1 binding and to prevent PD-L1 inhibitory functions. Since CTLA-4 is known to capture and degrade its ligands via transendocytosis, we investigated the interplay between CD80 transendocytosis and CD80/PD-L1 interaction. We find that transendocytosis of CD80 results in a time-dependent recovery of PD-L1 availability that correlates with CD80 removal. Moreover, CD80 transendocytosis is highly specific in that only CD80 is internalised, while its heterodimeric PD-L1 partner remains on the plasma membrane of the antigen-presenting cell (APC). CTLA-4 interactions with CD80 do not appear to be inhibited by PD-L1, but efficient removal of CD80 requires an intact CTLA-4 cytoplasmic domain, distinguishing this process from more general trogocytosis and simple CTLA-4 binding to CD80/PD-L1 complexes. These data are consistent with CTLA-4 acting as modulator of PD-L1:PD-1 interactions via control of CD80.

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“…This population has also been observed in clinical trials of ipilimumab and is associated with longer survival. In CTLA‐4 gene knockout mice, multiple noncanonical T cell populations can be found that are not observed in wild‐type mice, including the ICOS + T H 1‐like effector cells seen with anti‐CTLA‐4 treatment 49 …”

Section: Effect Of Checkpoint Inhibitors On T Cell Populationsmentioning

confidence: 99%

Frontiers in cancer immunotherapy—a symposium report

Cable¹,

Greenbaum

Pe’er

et al. 2020

Annals of the New York Academy of Sciences

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Cancer immunotherapy has dramatically changed the approach to cancer treatment. The aim of targeting the immune system to recognize and destroy cancer cells has afforded many patients the prospect of achieving deep, long‐term remission and potential cures. However, many challenges remain for achieving the goal of effective immunotherapy for all cancer patients. Checkpoint inhibitors have been able to achieve long‐term responses in a minority of patients, yet improving response rates with combination therapies increases the possibility of toxicity. Chimeric antigen receptor T cells have demonstrated high response rates in hematological cancers, although most patients experience relapse. In addition, some cancers are notoriously immunologically “cold” and typically are not effective targets for immunotherapy. Overcoming these obstacles will require new strategies to improve upon the efficacy of current agents, identify biomarkers to select appropriate therapies, and discover new modalities to expand the accessibility of immunotherapy to additional tumor types and patient populations.

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Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States

Cited by 5 publications

References 0 publications

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

The CTLA‐4 immune checkpoint protein regulates PD‐L1:PD‐1 interaction via transendocytosis of its ligand CD80

Frontiers in cancer immunotherapy—a symposium report

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