Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses

Bayerl, Felix; Meiser, Philippa; Donakonda, Sainitin; Hirschberger, Anna; Lacher, Sebastian; Pedde, Anna-Marie; Hermann, Chris D.; Elewaut, Anais; Knolle, Moritz; Ramsauer, Lukas; Rudolph, Thomas; Grassmann, Simon; Öllinger, Rupert; Kirchhammer, Nicole; Trefny, Marcel P.; Anton, Martina; Wohlleber, Dirk; Höchst, Bastian; Zaremba, Anne; Krüger, Achim; Rad, Roland; Obenauf, Anna C.; Schadendorf, Dirk; Zippelius, Alfred; Buchholz, Veit R.; Schraml, Barbara U.; Böttcher, Jan

doi:10.1016/j.immuni.2023.05.011

Cited by 50 publications

(35 citation statements)

References 79 publications

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“…25 This association has been found to be predictive of patient survival and responsiveness to immunotherapy with checkpoint inhibitors 26,27 across different tumor types, including luminal breast cancer (LBC) 28 and melanoma. 29 All these pieces of work collectively demonstrated a notable correlation between an augmented expression of the functional cDC1 signature and enhanced patient survival and responsiveness to immunotherapy. These findings highlight the importance of considering not only the quantity but also the functional state of cDC1 to predict patient outcomes.…”

Section: C1 Cell S In Antic An Cer Immunit Ymentioning

confidence: 93%

Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Luri‐Rey,

Gomis,

Glez‐Vaz

et al. 2023

Immunological Reviews

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SummaryAntigen cross‐priming of CD8+ T cells is a critical process necessary for the effective expansion and activation of CD8+ T cells endowed with the ability to recognize and destroy tumor cells. The cross‐presentation of tumor antigens to cross‐prime CD8+ T cells is mainly mediated, if not only, by a subset of professional antigen‐presenting cells termed type‐1 conventional dendritic cells (cDC1). The demise of malignant cells can be immunogenic if it occurs in the context of premortem stress. These ways of dying are termed immunogenic cell death (ICD) and are associated with biochemical features favoring cDC1 for the efficient cross‐priming of tumor antigens. Immunosurveillance and the success of immunotherapies heavily rely on the ability of cytotoxic immune cells, primarily CD8+ T cells and NK cells, to detect and eliminate tumor cells through mechanisms collectively known as cytotoxicity. Recent studies have revealed the significance of NK‐ and CTL‐mediated cytotoxicity as a prominent form of immunogenic cell death, resulting in mechanisms that promote and sustain antigen‐specific immune responses. This review focuses on the mechanisms underlying the cross‐presentation of antigens released during tumor cell killing by cytotoxic immune cells, with an emphasis on the role of cDC1 cells. Indeed, cDC1s are instrumental in the effectiveness of most immunotherapies, underscoring the significance of tumor antigen cross‐priming in contexts of immunogenic cell death. The notion of the potent immunogenicity of cell death resulting from NK or cytotoxic T lymphocyte (CTL)‐mediated cytotoxicity has far‐reaching implications for cancer immunotherapy.

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Section: C1 Cell S In Antic An Cer Immunit Ymentioning

confidence: 93%

Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Luri‐Rey,

Gomis,

Glez‐Vaz

et al. 2023

Immunological Reviews

View full text Add to dashboard Cite

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“…Of note, PGE2 is elevated in many cancers, which suppresses the antitumor functions of other immune cells include NK cells, T cells and DCs. 10,88,124,125 Hence, PGE2 metabolism may be a preferable target in tumor immunotherapies due to its broad suppression to antitumor immune cells. Hence, tumor cell metabolism-derived nutrient restrictions and toxic metabolites can profoundly suppress the antitumor functions of both NK cells and neutrophils, and promote immunosuppressive M2-like TAMs and TANs, to further inhibit adaptive antitumor immunity (Figure .…”

Section: Tumor Cell Metabolism and Immunosuppressionmentioning

confidence: 99%

“…86 PGE2 induces cDC1 dysfunction, inhibits the accumulation of cDCs and suppresses the maturation of tumor-infiltrating DCs. 87,88 Mature DCs enriched in immunoregulatory molecules (mregDCs) are a type of DC identified as generating both immunostimulatory and immunoregulatory molecules. 89 PGE2 was recently demonstrated to drive mregDC recruitment of T reg via PGE2-EP2/EP4 signaling.…”

Section: Tumor Cell Metabolism and Immunosuppressionmentioning

confidence: 99%

“…Further, oxidized lipids, including oxidized triglycerides, cholesterol esters, and fatty acids, can block DC cross-presentation by reducing the expression of peptide-MHC I complexes on the cell surface . PGE2 induces cDC1 dysfunction, inhibits the accumulation of cDCs and suppresses the maturation of tumor-infiltrating DCs. , Mature DCs enriched in immunoregulatory molecules (mregDCs) are a type of DC identified as generating both immunostimulatory and immunoregulatory molecules . PGE2 was recently demonstrated to drive mregDC recruitment of T reg via PGE2-EP2/EP4 signaling .…”

Section: Tumor Cell Metabolism and Immunosuppressionmentioning

confidence: 99%

“…Moreover, NK activation receptors can be repressed by hypoxia and PGE2. , Therefore, targeting tumor metabolism or increasing the metabolic flexibility of NK cells may be effective strategies for enhancing NK cell antitumor immunity. Of note, PGE2 is elevated in many cancers, which suppresses the antitumor functions of other immune cells include NK cells, T cells and DCs. ,,, Hence, PGE2 metabolism may be a preferable target in tumor immunotherapies due to its broad suppression to antitumor immune cells.…”

Section: Tumor Cell Metabolism and Immunosuppressionmentioning

confidence: 99%

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Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

Zhou,

Yuan,

et al. 2024

ACS Nano

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Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by accumulation of toxic metabolites and depletion of various nutrients, which significantly hinder the antitumor immunity via multiple mechanisms, hindering the efficacy of tumor immunotherapies. In-depth investigation of the mechanisms underlying these phenomena are vital for developing effective antitumor drugs and therapies, while the therapeutic effects of metabolism-targeting drugs are restricted by off-target toxicity toward effector immune cells and high dosage-mediated side effects. Nanotechnologies, which exhibit versatility and plasticity in targeted delivery and metabolism modulation, have been widely applied to boost tumor immunometabolic therapies via multiple strategies, including targeting of metabolic pathways. In this review, recent advances in understanding the roles of tumor cell metabolism in both immunoevasion and immunosuppression are reviewed, and nanotechnologybased metabolic reprogramming strategies for enhanced tumor immunotherapies are discussed.

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Multiplexed imaging to reveal tissue dendritic cell spatial localisation and function

Rocca,

Galli,

Celant

et al. 2024

FEBS Letters

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Dendritic cells (DCs) play a pivotal role in immune surveillance, acting as sentinels that coordinate immune responses within tissues. Although differences in the identity and functional states of DC subpopulations have been identified through multiparametric flow cytometry and single‐cell RNA sequencing, these methods do not provide information about the spatial context in which the cells are located. This knowledge is crucial for understanding tissue organisation and cellular cross‐talk. Recent developments in multiplex imaging techniques can now offer insights into this complex spatial and functional landscape. This review provides a concise overview of these imaging methodologies, emphasising their application in identifying DCs to delineate their tissue‐specific functions and aiding newcomers in navigating this field.

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Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses

Cited by 50 publications

References 79 publications

Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

Multiplexed imaging to reveal tissue dendritic cell spatial localisation and function

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