Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines

Kang, Jee Hye; Bluestone, Jeffrey A.; Young, Arabella

doi:10.1016/j.it.2021.02.006

Cited by 79 publications

(69 citation statements)

References 122 publications

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“…There is evidence from clinical studies to suggest that IL-17A signaling undermines immune checkpoint inhibitors, contributes to immunotherapy resistance and promotes the development of adverse autoimmune events in cancer patients (Kang et al, 2021). As such, modulation of PD-1 and TIM-3 in cancer patients and the impact of inhibiting these molecules on γδ T cells is a point for consideration, as these immunotherapy drugs may deleteriously increase IL-17A expression and immunosuppressive neutrophil activation.…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Hedley

Whm

et al. 2021

Preprint

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IL-17A-producing γδ T cells within the lung consist of both Vγ6+ tissue-resident cells and Vγ4+ circulating cells that play important roles in homeostasis, inflammation, infection, tumor progression and metastasis. How these γδ T cell subsets are regulated in the lung environment during homeostasis and cancer remains poorly understood. Using single-cell RNA sequencing and flow cytometry, we show that lung Vγ6+ cells express a repertoire of cell surface molecules distinctive from Vγ4+ cells, including PD-1 and ICOS. We found that PD-1 functions as a co-inhibitory molecule on Vγ6+ cells to reduce IL-17A production, whereas manipulation of ICOS signaling fails to affect IL-17A in Vγ6+ cells. In a mammary tumor model, ICOS and PD-1 expression on lung Vγ6+ cells remained stable. However, Vγ6+ and Vγ4+ cells within the lung pre-metastatic niche increased expression of IL-17A, IL-17F, amphiregulin (AREG) and TIM-3 in response to tumor-derived IL-1β and IL-23, where the upregulation of TIM-3 was specific to Vγ4+ cells. Inhibition of either PD-1 or TIM-3 in mammary tumor-bearing mice further increased IL-17A by Vγ6+ and Vγ4+ cells, indicating that both PD-1 and TIM-3 function as negative regulators of IL-17A-producing γδ T cell subsets. Together, these data demonstrate how lung γδ T cell subsets are differentially controlled by co-inhibitory molecules in steady-state and cancer.

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Section: Discussionmentioning

confidence: 99%

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Hedley

Whm

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Of note, one retrospective cohort correlated IL-8 levels with ICI-associated VTE, introducing the previously uncatalogued cytokine IL-8 into the long list of cytokines involved in ICI irAEs that are being examined as potential therapeutic targets that could permit ICI continuation in the face of highgrade toxicities typically managed by stopping the ICI. 43,44…”

Section: Thrombosismentioning

confidence: 99%

Hematologic complications of immune checkpoint inhibitors

Kroll¹,

Yee²,

Rojas‐Hernandez

2022

Blood

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Immune checkpoint inhibitors are a class of anti-neoplastic therapies that unleash immune cells to kill malignant cells. There are currently 7 medications FDA-approved for the treatment of 14 solid tumors and 2 hematological malignancies. These medications commonly cause immune-related adverse effects due to overactive T lymphocytes, autoantibody production, and/or cytokine dysregulation. Hematological toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses, such as autoimmune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia. Management is challenging because one must attend to the hematological toxicity while simultaneously attending to the malignancy, with the imperative that effective cancer therapy be maintained or minimally interrupted if possible. The purpose of this review is to assist clinicians by providing a clinical and pathophysiological framework in which to view these problems.

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“…Altogether, the described evidences demonstrate that NK cells are dysfunctional in cancer patients and that their reinvigoration appears as feasible, and these findings are motorizing the development of novel ICI aimed at leveraging NK cell mediated effector functions ( 177 ). However, targeting co-inhibitory receptors has a dark side as treatment with ICI can trigger many cytokine-mediated immune-related adverse events (irAE) that can be severe and require interruption of ICI treatment and/or complementary treatment with other compounds ( 199 – 203 ). Moreover, the description of patients with accelerated tumor growth after treatment with ICI (hyperprogression) due to ill-defined mechanisms is an additional concern ( 5 – 7 ).…”

Section: Nk Cell Reinvigoration Through Targeting Co-inhibitory Receptorsmentioning

confidence: 99%

Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines

Cited by 79 publications

References 122 publications

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

Hematologic complications of immune checkpoint inhibitors

Leveraging NKG2D Ligands in Immuno-Oncology

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