Fabrication of Methylene Blue Loaded Ovalbumin/Polypyrrole Nanoparticles for Enhanced Phototherapy-Triggered Antitumor Immune Activation

Abstract Phototherapy-triggered immunogenic cell death (ICD) hardly elicit robust antitumor immune response partially due to low antigen exposure and inefficient antigen presentation. To address these issues, we developed a novel methylene blue loaded ovalbumin/ polypyrrole nanoparticles (MB@OVA/PPY NPs) via oxidative polymerization and π-π stacking reaction. The as-prepared MB@OVA/PPY NPs with outstanding photothermal conversion efficiency (38%) and photodynamic property could be readily internalized into cytoplasm and accumulated in lysosome and mitochondria. Upon 808 nm and 660 nm laser irradiation, the MB@OVA/PPY NPs not only ablated the tumor cells by inducing local hyperthermia, but also damaged residual tumor cells by generating a large amount of reactive oxygen species (ROS), finally triggered the release of large amount of damage associated molecular patterns (DAMPs). Moreover, the MB@OVA/PPY NPs synergized with DAMPs promoted thematuration and improved antigen presentation ability of DCs in virto and vivo. This work demonstrated that the MB@OVA/PPY NPs could be used as effective nanotherapeutic agents for eliminating the solid tumor and triggering powerful antitumor immune response.

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Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

Cancers ◽

10.3390/cancers13143386 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3386

Author(s):

Bart Spiesschaert ◽

Katharina Angerer ◽

John Park ◽

Guido Wollmann

Keyword(s):

Immune Response ◽

Immune Responses ◽

Tumor Cells ◽

Small Molecule ◽

Antiviral Immunity ◽

Oncolytic Viruses ◽

Antitumor Immune Response ◽

Antiviral Responses ◽

Small Molecule Therapeutics ◽

Immunosuppressive Factors

The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

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Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽

10.3390/cancers13112566 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2566

Author(s):

María Julia Lamberti ◽

Annunziata Nigro ◽

Vincenzo Casolaro ◽

Natalia Belén Rumie Vittar ◽

Jessica Dal Col

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cell Activation ◽

Adaptive Immune Response ◽

Current Status ◽

Immunogenic Cell Death ◽

Basal Expression ◽

Antigen Presenting ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

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Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽

10.3390/cells10040930 ◽

2021 ◽

Vol 10 (4) ◽

pp. 930

Author(s):

Rianne D. W. Vaes ◽

Lizza E. L. Hendriks ◽

Marc Vooijs ◽

Dirk De Ruysscher

Keyword(s):

Cell Death ◽

Immune Responses ◽

Tumor Cells ◽

Immunogenic Cell Death ◽

Type I ◽

Future Studies ◽

Regulated Cell Death ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

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2. First responders: the innate immune response

The Immune System: A Very Short Introduction ◽

10.1093/actrade/9780198753902.003.0002 ◽

2017 ◽

pp. 17-29

Author(s):

Paul Klenerman

Keyword(s):

Immune Response ◽

Immune System ◽

Innate Immune Response ◽

Acute Phase Response ◽

First Responders ◽

Fundamental Question ◽

Innate Immune ◽

Rapid Action ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

How does the immune system know when to respond? ‘First responders: the innate immune response’ considers this fundamental question that is central to understanding both normal (e.g. to infections) and abnormal (e.g. in auto-immune diseases) responses; and designing vaccines and new therapies in cancer and infectious diseases. It looks at how ‘danger’ is sensed by the immune system through pathogen-associated molecular patterns and damage-associated molecular patterns. Having been alerted, it is important that rapid action is taken to limit the spread of a pathogen. A number of responses can be initiated immediately, forming a critical part of our innate immunity, which are followed by the acute phase response.

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Production of Adenosine by Ectonucleotidases: A Key Factor in Tumor Immunoescape

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/473712 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 47

Author(s):

François Ghiringhelli ◽

Mélanie Bruchard ◽

Fanny Chalmin ◽

Cédric Rébé

Keyword(s):

Immune Response ◽

Cancer Cells ◽

Tumor Cells ◽

Stromal Cells ◽

T Cell Response ◽

Antitumor Immune Response ◽

Tumor Bed ◽

Wide Range ◽

Key Factor ◽

The Impact

It is now well known that tumor immunosurveillance contributes to the control of cancer growth. Many mechanisms can be used by cancer cells to avoid the antitumor immune response. One such mechanism relies on the capacity of cancer cells or more generally of the tumor microenvironment to generate adenosine, a major molecule involved in antitumor T cell response suppression. Adenosine is generated by the dephosphorylation of extracellular ATP released by dying tumor cells. The conversion of ATP into adenosine is mediated by ectonucleotidase molecules, namely, CD73 and CD39. These molecules are frequently expressed in the tumor bed by a wide range of cells including tumor cells, regulatory T cells, Th17 cells, myeloid cells, and stromal cells. Recent evidence suggests that targeting adenosine by inhibiting ectonucleotidases may restore the resident antitumor immune response or enhance the efficacy of antitumor therapies. This paper will underline the impact of adenosine and ectonucleotidases on the antitumor response.

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Control of the Antitumor Immune Response by Cancer Metabolism

Cells ◽

10.3390/cells8020104 ◽

2019 ◽

Vol 8 (2) ◽

pp. 104 ◽

Cited By ~ 17

Author(s):

Charlotte Domblides ◽

Lydia Lartigue ◽

Benjamin Faustin

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Cancer Metabolism ◽

Hematological Malignancies ◽

Immune Cell ◽

Immune Escape ◽

Positive Impact ◽

Metabolic Reprogramming ◽

Antitumor Immune Response ◽

Molecular Events

The metabolic reprogramming of tumor cells and immune escape are two major hallmarks of cancer cells. The metabolic changes that occur during tumorigenesis, enabling survival and proliferation, are described for both solid and hematological malignancies. Concurrently, tumor cells have deployed mechanisms to escape immune cell recognition and destruction. Additionally, therapeutic blocking of tumor-mediated immunosuppression has proven to have an unprecedented positive impact in clinical oncology. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune signaling through both the release of signaling molecules and the expression of immune membrane ligands. Here, we review these molecular events to highlight the contribution of cancer cell metabolic reprogramming on the shaping of the antitumor immune response.

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Vaccination with CD47 deficient tumor cells elicits an antitumor immune response in mice

Nature Communications ◽

10.1038/s41467-019-14102-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 5

Author(s):

Yang Li ◽

Mingyou Zhang ◽

Xiaodan Wang ◽

Wentao Liu ◽

Hui Wang ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Antitumor Immune Response

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Taking Advantage of Plant Defense Mechanisms to Promote Human Health. The Plant Immune System. First of Two Parts

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320999200831224302 ◽

2020 ◽

Vol 20 ◽

Author(s):

Thea Magrone ◽

Manrico Magrone ◽

Matteo Antonio Russo ◽

Emilio Jirillo

Keyword(s):

Immune Response ◽

Plant Defense ◽

Defense Mechanisms ◽

Systemic Acquired Resistance ◽

Plant Immunity ◽

Acquired Resistance ◽

Early Response ◽

Protein Receptors ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Background: Despite the evidence that plants do not possess sessile cells, they are able to mount a vigorous immune response against invaders or under stressful conditions. Mechanisms of action: Plants are endowed with pattern recognition receptors (PPRs) which perceive damage-associated molecular patterns and microbe-associated molecular patterns or pathogen-associated molecular patterns (PAMPs), respectively. PPR activation leads to either the initiation of PAMP-triggered immunity (PTI) (early response) or the effectortriggered immunity (ETI). Both PTI and ETI contribute to plant systemic acquired resistance as also an expression of immunological memory or trained immunity. Plant immune receptors: PTI is initiated by activation of both receptor-like kinases and receptor-like proteins, while ETI depends on nucleotide-binding leucine-rich-repeat protein receptors for microbe recognition. Peptides involved in plant defenses: Plant chloroplasts contribute to both PTI and ETI through production of peptides which act as hormones or phytocytokines. Salicylic acid, jasmonic acid and ethylene are the major compounds involved in plant defense. Specific aims: The interaction between plant receptors and/or their products and bacterial components will be discussed. Also emphasis will be placed on plant microbiome for its contribution to plant immune response. Finally, the mutual interplay between insects and plants will also be illustrated. Conclusion: A better knowledge on plant immunity may pave the way for the exploitation of plant derivatives in the field of agriculture and medicine, as well.

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Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23087 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23087-e23087

Author(s):

Anne Jarry ◽

Adrien Ouairy ◽

Delphine Dansette ◽

Cécile Deleine ◽

Nicolas Jouand ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

T Lymphocytes ◽

Tumor Cells ◽

Retrospective Cohort ◽

Ex Vivo ◽

High Density ◽

Antitumor Immune Response ◽

Caspase 1 ◽

Active Caspase

e23087 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNγ) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with i) the microsatellite stable (MSS) or unstable (MSI) status of CRC, and ii) the levels of cytokines (IL18, IFNγ) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNγ response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNγ release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Rα), cultured with rhIL18, were able to secrete IFNγ either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.

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Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.640 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 640-640

Author(s):

Celine Bossard ◽

Delphine Dansette ◽

Adrien Ouairy ◽

Nicolas Jouand ◽

Romain Oger ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

T Lymphocytes ◽

Tumor Cells ◽

Retrospective Cohort ◽

Ex Vivo ◽

High Density ◽

Antitumor Immune Response ◽

Caspase 1 ◽

Active Caspase

640 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNg) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with the microsatellite stable (MSS) or unstable (MSI) status of CRC, and the levels of cytokines (IL18, IFNg) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNg response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNg release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Ra), cultured with rhIL18, were able to secrete IFNg either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.

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