Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors

Davar, Diwakar; Zarour, Hassane M.

doi:10.1007/978-1-4939-9773-2_2

Cited by 14 publications

(13 citation statements)

References 178 publications

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“…Especially the initial results from the ongoing phase II study TACTI-002 on the combination of pembrolizumab with soluble LAG-3 protein showing overall response rates of 47%, are very promising ( 51 ). While most studies revealed the suppressive role of VISTA, LAG-3, and TIM-3 role in the context of T cell exhaustion ( 52 ), we uncover their suppressive role on lung tumor-infiltrated monocytes as well. Moreover, we demonstrate their upregulation of ‘don’t eat me signal’ SIRP-α too, previously shown to hamper phagocytosis upon ligation to CD47 on lung tumor cells ( 53 – 56 ).…”

Section: Discussionmentioning

confidence: 58%

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy

et al. 2022

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Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1+ NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1+ tumor-infiltrating myeloid cells in therapy failure. As the latter comprise a heterogenous population in the lung tumor microenvironment, we applied an orthotopic Lewis Lung Carcinoma (LLC) model to evaluate 11 different tumor-residing myeloid subsets in response to anti-PD-L1 therapy. While we observed significantly reduced fractions of tumor-infiltrating MHC-IIlow macrophages and monocytes, serological levels of TNF-α restored in lung tumor-bearing mice. Notably, we demonstrated in vivo and in vitro that anti-PD-L1 therapy mediated a monocyte-specific production of, and response to TNF-α, further accompanied by their significant upregulation of CD80, VISTA, LAG-3, SIRP-α and TIM-3. Nevertheless, co-blockade of PD-L1 and TNF-α did not reduce LLC tumor growth. A phenomenon that was partly explained by the observation that monocytes and TNF-α play a Janus-faced role in anti-PD-L1 therapy-mediated CTL stimulation. This was endorsed by the observation that monocytes appeared crucial to effectively boost T cell-mediated LLC killing in vitro upon combined PD-L1 with LAG-3 or SIRP-α blockade. Hence, this study enlightens the biomarker potential of lung tumor-infiltrated monocytes to define more effective ICB combination strategies.

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Section: Discussionmentioning

confidence: 58%

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy

et al. 2022

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“…This may well lead to the identification of new treatment targets, in addition to deepening our understanding of autoimmunity. Potential treatment targets include immune populations; signaling pathways of various ICIs targeting negative immune receptors (108); and secreted factors that are expanded/amplified at the initiation of the inflammatory toxicity and diminish during disease resolution, but that may not be apparent in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Time to dissect the autoimmune etiology of cancer antibody immunotherapy

Dougan¹,

Pietropaolo²

2020

Journal of Clinical Investigation

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that are recruited into the immunologic synapse (2). The degree of CTLA-4 recruitment to the immunologic synapse correlates with TCR signal strength, and it is stabilized by B7 ligand binding and outcompetes CD28 (14). Through this mechanism, CTLA-4 dampens positive costimulation by CD28 and in turn decreases CD28 downstream signaling that is primarily mediated by PI3K and AKT (15, 16). CTLA-4 regulation of T cell activity takes place not only in lymphoid organs but also in peripheral tissues, given that B7 ligands are expressed (to a certain extent) by antigenpresenting cells within tissues, including tumors, and can also be expressed by activated T cells. The primary biological function of the PD-1/PD-L1 pathway is to maintain peripheral tolerance in the setting of chronic inflammation. PD-1, like CTLA-4, is expressed after T cell activation, but its expression increases upon repeated stimulation (17). PD-1 has also been found on several other cell types, including B cells (17). PD-L1 is upregulated by inflammatory cytokines such as IFN-γ on a wide variety of tissues, including many tumors (18-20). A second ligand for PD-1, PD-L2, is expressed primarily on cells of hematologic origin. PD-1 and its ligand PD-L1 exhibit a critical role in tumor progression and appear to play a central role in mediating tumor immune escape. PD-1 regulates T cell activation through interaction with PD-L1 and PD-L2 (Figure 1 and Figure 2A) (18-20). Upon engagement with PD-L1 and PD-L2, PD-1 delivers a negative costimulatory signal through the tyrosine phosphatase SHP2, leading to diminished activation. The recruitment of SHP2 directly attenuates TCR signaling through dephosphorylation of proximal signaling elements (Figure 1). Recently it has been shown that CD28 is an important target for PD-1-induced attenuation of T cell signaling (21).

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Section: Methodsmentioning

confidence: 99%

“…In a subset comprising n = 6 patients, we evaluated the surface expression of certain molecules relevant to the immune response on PBMCs, known to play a part in the antitumoral immunity and the efficacy of ICI therapy. 11,16 To differentially investigate the lymphocyte subpopulations in the peripheral blood, we used multicolor flow cytometry analysis. Since T-cell-mediated cytotoxicity, mainly by cytotoxic T lymphocytes (CTL), expressing CD3 and CD8 at the cell surface, is considered the most important axis in lymphocyteassociated tumor control, we next focused on the CTL response in more detail, checking for cell-bound BTLA on different T-cell populations, taking special interest in CD3 + CD8 + BTLA+ cells.…”

Section: Evaluation Of Btla Surface Expression Of Pbmcs With Multicol...mentioning

confidence: 99%

“…This domain binds to the herpes virus entry mediator (HVEM), a protein of the tumor necrosis factor family, which is also widely expressed in a variety of immune cells. 10 Upon activation, BTLA acts identically or even synergistically to PD-1 and CTLA-4, delivering a co-inhibitory signal that leads to T-cell inhibition and anergy, playing an irrefutable role in modulating the immune response against cancers, 11 and possibly in influencing the effectiveness of ICIbased cancer immunotherapy. Its soluble form, sBTLA, has previously been described as a promising biomarker in the landscape of sepsis, inflammation 12 and cancer, 13,14 but its role in the context of ICI has remained obscure.…”

Section: Introductionmentioning

confidence: 99%

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Serum levels of soluble B and T lymphocyte attenuator predict overall survival in patients undergoing immune checkpoint inhibitor therapy for solid malignancies

Gorgulho

Roderburg

Heymann

et al. 2021

Intl Journal of Cancer

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Therapy with immune checkpoint inhibitors (ICIs) can lead to durable tumor control in patients with various advanced stage malignancies. However, this is not the case for all patients, leading to an ongoing search for biomarkers predicting response and outcome to ICI. The B and T lymphocyte attenuator (BTLA) is an immune checkpoint expressed on immune cells that was shown to modulate therapeutic responses. Here, we evaluate circulating levels of its soluble form, soluble B and T lymphocyte attenuator (sBTLA), as a biomarker for the prediction of treatment response and outcome to ICI therapy. Serum levels of sBTLA were analyzed by multiplex immunoassay in n = 84 patients receiving ICI therapy for solid malignancies and 32 healthy controls. BTLA expression was evaluated on peripheral blood mononuclear cells in a subset of patients (n = 6) using multicolor flow cytometry. Baseline sBTLA serum levels were significantly higher in cancer patients compared to healthy controls. Importantly, circulating sBTLA levels were an

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Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors

Cited by 14 publications

References 178 publications

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy

Time to dissect the autoimmune etiology of cancer antibody immunotherapy

Serum levels of soluble B and T lymphocyte attenuator predict overall survival in patients undergoing immune checkpoint inhibitor therapy for solid malignancies

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