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4 pages, 218 KiB

Open AccessEditorial

Immunogenic Cell Stress and Death Sensitize Tumors to Immunotherapy

by Oliver Kepp and Guido Kroemer

Cells 2023, 12(24), 2843; https://doi.org/10.3390/cells12242843 - 15 Dec 2023

Cited by 2 | Viewed by 1471

Abstract

The efficacy of chemotherapy with cytotoxicants and that of targeted therapies with more sophisticated agents is limited due to the plasticity of malignant cells, which leads to the inevitable development of resistance [...] Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

Research

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19 pages, 3466 KiB

Open AccessArticle

Panobinostat Induced Spatial In Situ Biomarkers Predictive of Anti-PD-1 Efficacy in Mouse Mammary Carcinoma

by Zuzana Tatarova, Dylan C. Blumberg, AeSoon Bensen, Gordon B. Mills and Oliver Jonas

Cells 2023, 12(2), 308; https://doi.org/10.3390/cells12020308 - 13 Jan 2023

Cited by 1 | Viewed by 3361

Abstract

Immunotherapies, including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of [...] Read more.

Immunotherapies, including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of cytotoxic and targeted agents. Reliable biomarkers predictive of the therapeutic response to ICB in breast cancer are critically missing, though a combination response has been associated with immunogenic cell death (ICD). Here, we utilized a recently developed integrated analytical platform, the multiplex implantable microdevice assay (MIMA), to evaluate the presence and spatial cell relations of literature-based candidate markers predictive of ICB efficacy in luminal mouse mammary carcinoma. MIMA integrates (i) an implantable microdevice for the localized delivery of small amounts of drugs inside the tumor bed with (ii) sequential multiplex immunohistochemistry (mIHC) and spatial cell analysis pipelines to rapidly (within days) describe drug mechanisms of action and find predictive biomarkers in complex tumor tissue. We show that the expression of cleaved caspase-3, ICAM-1, neuropilin-1, myeloperoxidase, calreticulin, galectin-3, and PD-L1 were spatially associated with the efficacy of panobinostat, a pan-HDAC inhibitor that was previously shown to induce immunogenic cell death and synergize with anti-PD-1 in breast cancer. PD-L1 by itself, however, was not a reliable predictor. Instead, ICB efficacy was robustly identified through the in situ hotspot detection of galectin-3-positive non-proliferating tumor zones enriched in cell death and infiltrated by anti-tumor cytotoxic neutrophils positive for ICAM-1 and neuropilin-1. Such hotspots can be specifically detected using distance-based cluster analyses. Single-cell measurements of the functional states in the tumor microenvironment suggest that both qualitative and quantitative effects might drive effective therapy responses. Overall, the presented study provides (i) complementary biological knowledge about the earliest cell events of induced anti-tumor immunity in breast cancer, including the emergence of resistant cancer stem cells, and (ii) newly identified biomarkers in form of specific spatial cell associations. The approach used standard cell-type-, IHC-, and FFPE-based techniques, and therefore the identified spatial clustering of in situ biomarkers can be readily integrated into existing clinical or research workflows, including in luminal breast cancer. Since early drug responses were detected, the biomarkers could be especially applicable to window-of-opportunity clinical trials to rapidly discriminate between responding and resistant patients, thus limiting unnecessary treatment-associated toxicities. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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24 pages, 3115 KiB

Open AccessArticle

The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response

by Justine De Azevedo, Jana Mourtada, Cyril Bour, Véronique Devignot, Philippe Schultz, Christian Borel, Erwan Pencreach, Georg Mellitzer, Christian Gaiddon and Alain C. Jung

Cells 2022, 11(18), 2866; https://doi.org/10.3390/cells11182866 - 14 Sep 2022

Cited by 6 | Viewed by 3069

Abstract

(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. [...] Read more.

(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies. (2) Methods: Using human HNSCC cell line models and a mouse oral cancer syngeneic model, we have analyzed the ability of the EXTREME regimen (combination therapy using the anti-EGFR cetuximab antibody and platinum-based chemotherapy) to modify the immunogenicity of HNSCC cells. (3) Results: We showed that the combination of cetuximab and cisplatin reduces cell growth through both cell cycle inhibition and the induction of apoptotic cell death independently of p53. In addition, different components of the EXTREME regimen were found to induce, to a variable extent, and in a cell-dependent manner, the emission of mediators of immunogenic cell death, including calreticulin, HMGB1, and type I Interferon-responsive chemokines. Interestingly, cetuximab alone or combined with the IC₅₀ dose of cisplatin can induce an antitumor immune response in vivo, but not when combined with a high dose of cisplatin. (4) Conclusions: Our observations suggest that the EXTREME protocol or cetuximab alone are capable, under conditions of moderate apoptosis induction, of eliciting the mobilization of the immune system and an anti-tumor immune response in HNSCC. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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Review

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22 pages, 1310 KiB

Open AccessEditor’s ChoiceReview

The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

by Isaure Vanmeerbeek, Jannes Govaerts, Raquel S. Laureano, Jenny Sprooten, Stefan Naulaerts, Daniel M. Borras, Damya Laoui, Massimiliano Mazzone, Jo A. Van Ginderachter and Abhishek D. Garg

Cells 2022, 11(23), 3890; https://doi.org/10.3390/cells11233890 - 2 Dec 2022

Cited by 13 | Viewed by 6298

Abstract

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer [...] Read more.

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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21 pages, 1414 KiB

Open AccessReview

In Vitro Veritas: From 2D Cultures to Organ-on-a-Chip Models to Study Immunogenic Cell Death in the Tumor Microenvironment

by Dmitri V. Krysko, Robin Demuynck, Iuliia Efimova, Faye Naessens, Olga Krysko and Elena Catanzaro

Cells 2022, 11(22), 3705; https://doi.org/10.3390/cells11223705 - 21 Nov 2022

Cited by 10 | Viewed by 3370

Abstract

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in [...] Read more.

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in vivo on mice, translation into the clinic remains challenging. A major hindrance in antitumor research is the poor predictive ability of classic 2D in vitro models, which do not consider tumor biological complexity, such as the contribution of the tumor microenvironment (TME), which plays a crucial role in immunosuppression and cancer evasion. In this review, we describe different tumor models, from 2D cultures to organ-on-a-chip technology, as well as spheroids and perfusion bioreactors, all of which mimic the different degrees of the TME complexity. Next, we discuss how 3D cell cultures can be applied to study ICD and how to increase the translational potential of the ICD inducers. Finally, novel research directions are provided regarding ICD in the 3D cellular context which may lead to novel immunotherapies for cancer. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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24 pages, 9348 KiB

Open AccessReview

Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

by Nicolas Roussot, François Ghiringhelli and Cédric Rébé

Cells 2022, 11(22), 3672; https://doi.org/10.3390/cells11223672 - 18 Nov 2022

Cited by 23 | Viewed by 3640

Abstract

The success of anticancer treatments relies on a long-term response which can be mediated by the immune system. Thus, the concept of immunogenic cell death (ICD) describes the capacity of dying cancer cells, under chemotherapy or physical stress, to express or release danger-associated [...] Read more.

The success of anticancer treatments relies on a long-term response which can be mediated by the immune system. Thus, the concept of immunogenic cell death (ICD) describes the capacity of dying cancer cells, under chemotherapy or physical stress, to express or release danger-associated molecular patterns (DAMPs). These DAMPs are essential to activate dendritic cells (DCs) and to stimulate an antigen presentation to CD8 cytotoxic cells. Then, activated CD8 T cells exert their antitumor effects through cytotoxic molecules, an effect which is transitory due to the establishment of a feedback loop leading to T-cell exhaustion. This phenomenon can be reversed using immune checkpoint blockers (ICBs), such as anti-PD-1, PD-L1 or CTLA-4 Abs. However, the blockade of these checkpoints is efficient only if the CD8 T cells are recruited within the tumor. The CD8 T-cell chemoattraction is mediated by chemokines. Hence, an important question is whether the ICD can not only influence the DC activation and resulting CD8 T-cell activation but can also favor the chemokine production at the tumor site, thus triggering their recruitment. This is the aim of this review, in which we will decipher the role of some chemokines (and their specific receptors), shown to be released during ICD, on the CD8 T-cell recruitment and antitumor response. We will also analyze the clinical applications of these chemokines as predictive or prognostic markers or as new targets which should be used to improve patients’ response. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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12 pages, 935 KiB

Open AccessReview

Immunogenic Cell Death: An Emerging Target in Gastrointestinal Cancers

by Marta Chiaravalli, Alexia Spring, Antonio Agostini, Geny Piro, Carmine Carbone and Giampaolo Tortora

Cells 2022, 11(19), 3033; https://doi.org/10.3390/cells11193033 - 28 Sep 2022

Cited by 24 | Viewed by 4338

Abstract

Immunogenic cell death (ICD) is a regulated form of cell death that induces the activation of both innate and adaptive immune responses through the release of damage-associated molecular patterns (DAMPs) and their subsequent recognition by pattern-recognition receptors (PRRs), generating specific CD8+ T lymphocytes. [...] Read more.

Immunogenic cell death (ICD) is a regulated form of cell death that induces the activation of both innate and adaptive immune responses through the release of damage-associated molecular patterns (DAMPs) and their subsequent recognition by pattern-recognition receptors (PRRs), generating specific CD8+ T lymphocytes. Thus, ICD inducers (such as certain chemotherapeutic agents, targeted therapies, radiation, and oncolytic viruses) could become a potential cancer treatment by providing antitumour immunity and cancer vaccination. Moreover, their combination with immunotherapy, especially with immune checkpoint inhibitors, could overcome the immunosuppressive tumour microenvironment that characterises certain cancers, including gastrointestinal cancers. This review will provide insights into the role of ICD induction in colorectal, gastric, pancreatic, and hepatocellular carcinomas. Specifically, we will discuss the main mechanisms involved in ICD, their potential application in gastrointestinal cancer treatment, and the latest clinical trial updates. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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19 pages, 2060 KiB

Open AccessFeature PaperReview

The “Yin and Yang” of Unfolded Protein Response in Cancer and Immunogenic Cell Death

by Nicole Rufo, Yihan Yang, Steven De Vleeschouwer and Patrizia Agostinis

Cells 2022, 11(18), 2899; https://doi.org/10.3390/cells11182899 - 16 Sep 2022

Cited by 9 | Viewed by 4117

Abstract

Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging [...] Read more.

Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging trait of cancer cells. Maladaptive UPR sustains oncogene-driven reprogramming of proteostasis and metabolism and fosters proinflammatory pathways promoting tissue repair and protumorigenic immune responses. However, when cancer cells are exposed to conditions causing irreparable ER homeostasis, such as those elicited by anticancer therapies, the UPR switches from a survival to a cell death program. This lethal ER stress response can elicit immunogenic cell death (ICD), a form of cell death with proinflammatory traits favoring antitumor immune responses. How UPR-driven pathways transit from a protective to a killing modality with favorable immunogenic and proinflammatory output remains unresolved. Here, we discuss key aspects of the functional dichotomy of UPR in cancer cells and how this signal can be harnessed for therapeutic benefit in the context of ICD, especially from the aspect of inflammation aroused by the UPR. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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15 pages, 1461 KiB

Open AccessReview

Promises and Challenges of Immunogenic Chemotherapy in Multiple Myeloma

by Megan Johnstone, Delaney Vinaixa, Marcello Turi, Eugenio Morelli, Kenneth Carl Anderson and Annamaria Gulla

Cells 2022, 11(16), 2519; https://doi.org/10.3390/cells11162519 - 14 Aug 2022

Cited by 3 | Viewed by 2895

Abstract

Immunological tolerance of myeloma cells represents a critical obstacle in achieving long-term disease-free survival for multiple myeloma (MM) patients. Over the past two decades, remarkable preclinical efforts to understand MM biology have led to the clinical approval of several targeted and immunotherapeutic agents. [...] Read more.

Immunological tolerance of myeloma cells represents a critical obstacle in achieving long-term disease-free survival for multiple myeloma (MM) patients. Over the past two decades, remarkable preclinical efforts to understand MM biology have led to the clinical approval of several targeted and immunotherapeutic agents. Among them, it is now clear that chemotherapy can also make cancer cells “visible” to the immune system and thus reactivate anti-tumor immunity. This knowledge represents an important resource in the treatment paradigm of MM, whereas immune dysfunction constitutes a clear obstacle to the cure of the disease. In this review, we highlight the importance of defining the immunological effects of chemotherapy in MM with the goal of enhancing the clinical management of patients. This area of investigation will open new avenues of research to identify novel immunogenic anti-MM agents and inform the optimal integration of chemotherapy with immunotherapy. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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