Induction Of Immunogenic Cell Death Research Articles

Abstract 4883: Pan cancer transcriptomic response to tumor treating fields (TTFields)

Abstract Introduction: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is versatile with multiple mechanisms of action, including: anti-mitotic effects, downregulation of DNA double strand break repair, generation of replication stress, upregulation of autophagy, and induction of immunogenic cell death. In this research we were interested in identifying common responses to TTFields across cancer types. We addressed this by integrating whole transcriptome analyses of cancers from various origins. Methods: Control and TTFields-treated samples examined included gastric, ovarian, pancreatic, non-small cell lung carcinoma, and glioblastoma cell lines, pleural mesothelioma patient-derived cell lines, and a hepatocellular carcinoma animal model. A list of differentially expressed genes (DEGs) was generated from transcriptomics analysis. Gene Set Enrichment Analysis (GSEA) was conducted with the MSigDB, and additional pathway databases. Significantly overlapping pathways were identified using ActivePathways package, and an enrichment map was created according to the number of datasets supporting each pathway. Results: The response to TTFields showed a positive correlation of expression across different cell lines and indications, including in an animal model. Downregulation was seen in cell cycle related pathways - E2F targets, Myc targets, G2M checkpoint, and mitotic spindle - indicative of cell cycle arrest, which was mediated by increased expression of tumor suppressors. Several DNA repair pathways were downregulated, including nucleotide excision repair, base excision repair, and the Fanconi Anemia-BRCA pathway. Downregulation was also evident in nuclear envelope, DNA and RNA synthesis, metabolism of amino acids, translation, organelle organization, and splicing. Upregulation was observed in genes associated with the cytoskeleton, adhesion, extracellular proteins and transporters. In the majority of comparisons, an upregulation in the immune response was also observed. Conclusions: Transcriptomic analysis of datasets from different tumor types revealed common expression patterns and pathways involved in the responses to TTFields. Some of the identified pathways corroborate previously described mechanisms, whereas some reveal new potential mechanisms that require further investigation. Citation Format: Kerem Wainer-Katsir, Gitit Lavy-Shahaf, Hila Fishman, Hila Ena, Roni Frechtel-Gerzi, Antonia Martinez-Conde, Eyal Dor-On, Shiri Davidi, Sara Jacobovitch, Itai Tzchori, Yaara Porat, Lianghao Ding, Michael Story, Renfei Du, Ulf Kahlert, Laura Mannarino, Federica Mirimao, Monica Lupi, Maurizio D’Incalci, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Pan cancer transcriptomic response to tumor treating fields (TTFields). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4883.

Abstract 3228: Photodynamic priming enhances immunotherapy responses overcoming oncogenic drivers in pancreatic patient derived tumor organoids

Abstract Photodynamic therapy (PDT) is an anti-cancer therapy that utilizes light, a photoresponsive photosensitizer (PS), and oxygen to confer direct cytotoxicity or vascular damage. PDT alters the tumor microenvironment (TME) transiently in a process termed photodynamic priming (PDP), making it more receptive to subsequent therapies. Previous studies reported that PDP exerts immune stimulatory effects via the release of damage associated molecular patterns (DAMPs) as a potent inducer of immunogenic cell death. Pancreatic cancer (PC) is a lethal human malignancy with no curable treatments available thus far. The desmoplastic stroma in PC limits the delivery of therapeutic agents contributing to treatment resistance. More, the stroma promotes an immunosuppressive TME that leads to immune exclusion, which is largely responsible for the immunotherapy failure in PC. Therefore, there is an unmet need to find more effective combination therapies against PC. In this work, we evaluated whether PDP enhances anti-PD1 therapy response by modulating immunogenicity in PC patient-derived organoids (PDOs). Visudyne (PS) and varied light doses of 25-100 J/cm2 were used for PDP treatments. Our data showed light dose dependent cytotoxicity and the expression of DAMPs including HSP60, calreticulin and HMGB1 in PDOs. Gene expression analysis of PDP treated PDOs showed increases in IFNγ, TNFα and CXCL12 while decreases in PDL1, TGFβ1 and FOXP1. Coculture of healthy donor (HD) monocyte-derived dendritic cells (mDCs) for 24 h with PDOs treated with a sublethal dose of PDP (25 J/cm2) showed increased CD40, CD86 and MHC11 activation markers on mDCs. Addition of matched HD naïve T cells 24 h post mDC-PDO coculture led to the excessive activation of CD4+ and CD8+ T cells highlighted by the PD1 expression on T cells from 0 h of initial T cell coculture to 48 h. This led us to treat PDO-mDC-T cell cocultures at 0 h to 48 h of initial T cell coculture with the anti-PD1 monoclonal antibody, Pembrolizumab. The treatment response was measured by live imaging of PDO growth followed by the analysis of changes in PDO diameter/area from day 0 of PDP to day 7 post-PDP. There were significant decreases in PDO growth in cultures treated with PDP followed by Pembrolizumab at different time points compared to untreated PDOs, untreated PDO-mDC-T cell cocultures, PDOs treated with PDP alone, PDO-mDC-T cell cocultures treated with PDP only or PDO-mDC-T cell cocultures treated with anti-PD1 alone. Also, we sorted T cells from the same cocultures at day 7 of PDP for gene expression analysis of T cell activation markers. There was enhanced expression of IFNγ, TNFα, FAS ligand, Granzyme B, IL2 and IL21 in T cells collected from combination therapy treated cocultures compared to others. Lastly, our data show that PDP can enhance anti-PD1 immunotherapy responses providing insights into a combination therapy option to treat PDAC. Citation Format: Pushpamali De Silva, Demi Wekking, Joanna Joeun Choe, Dario Missael Castellanos, Piotr Zelga, Russell Jenkins, Andrew Scott Liss, Tayyaba Hasan. Photodynamic priming enhances immunotherapy responses overcoming oncogenic drivers in pancreatic patient derived tumor organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3228.

Abstract 632: Exploiting pyroptosis in melanoma brain metastasis

Abstract Melanoma is the deadliest form of skin cancer due to its frequent metastasis to the brain. Melanoma brain metastases (MBM) are a significant clinical challenge, and current model systems and therapeutic strategies are poor. Inhibitors targeting the most common oncogenic driver of melanoma, BRAFV600E (BRAFi), disrupt mitogenic signaling and promote caspase-3 associated cell death. Though caspase-3 is a well-known apoptotic driver, it can also cleave Gasdermin E (GSDME) to create pore-forming N-terminal fragments that oligomerize at plasma and mitochondrial membranes and trigger pyroptosis - a form of immunogenic cell death (ICD). Our recent work illustrates the importance of GSDME mediated pyroptosis and associated immunogenicity in providing a durable therapeutic response against melanoma. Since pyroptosis can be activated by GSDME cleavage via caspase-3, and is prominent in various neuropathologies, a better understanding of the interplay between central nervous system (CNS) immune cells and BRAFi-mediated ICD is critical for designing more effective therapies against MBM. Here, we engineered a panel of inducible pyroptotic melanoma cells to model BRAFi-mediated pyroptosis. Using ex vivo CNS slice co-cultures, we found that inducible N-GSDME expression in human and murine melanoma cells drives propidium iodide uptake and release of inflammatory activators like HMGB1 and IL-1 - hallmarks of pyroptosis. Importantly, conditioned media from these pyroptotic cells stimulates a more robust phagocytic response from resident macrophages of the CNS and pyroptotic melanoma elicit stronger cytotoxicity from syngeneic CD8+ T cells, further highlighting the benefits of BRAFi-mediated ICD. Our findings provide evidence that resident CNS immune cells and peripheral T cells respond to pyroptotic melanoma, suggesting that induction of ICD should be a consideration in the development of anti-MBM therapies. Citation Format: Maria R. Cavallo. Exploiting pyroptosis in melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 632.

Induction of immunogenic cell death effect of licoricidin in cervical cancer cells by enhancing endoplasmic reticulum stress-mediated high mobility group box 1 expression.

Licoricidin (LCD) is an activity compound of the roots of Glycyrrhiza uralensis, which has therapeutic efficacy, including anti-virus, anti-cancer, and enhanced immunity in Traditional Chinese Medicine. Herein, this study aimed to clarify the effect of LCD on cervical cancer cells. In the present study, we found that LCD significantly inhibited cell viability via inducing cell apoptosis and companies with cleaved-PARP protein expression and caspase-3/-9 activity. Cell viability was markedly reversed these effects by pan-caspase inhibitor Z-VAD-FMK treatment. Furthermore, we showed that LCD-induced ER (endoplasmic reticulum) stress triggers upregulating the protein level of GRP78 (Bip), CHOP, and IRE1α, and subsequently confirmed the mRNA level by quantitative real-time polymerase chain reaction. In addition, LCD exhibited the release of danger-associated molecular patterns from cervical cancer cells, such as the release of high-mobility group box 1 (HMGB1), secretion of ATP, and exposure of calreticulin (CRT) on the cell surface, which led to immunogenic cell death (ICD). These results provide a novel foundation that LCD induces ICD via triggering ER stress in human cervical cancer cells. LCD might be an ICD inducer of immunotherapy in progressive cervical cancer.

Abstract 2013: Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs

Abstract Novel payloads with orthogonal mechanisms of action (MOAs) to established ADC technologies are important for expanding the utility of antibody-drug conjugates (ADCs) in cancer treatment. Anthracyclines, a class of cytotoxic small molecules that include important clinical chemotherapeutics such as doxorubicin, have long been of interest to the ADC field due to their high potency and unique MOA. Interest in anthracyclines has increased in recent years due to their status as canonical inducers of immunogenic-cell death (ICD), a feature that may lead to more durable tumor regressions and increased synergy with immune checkpoint blockade. In this work, we investigate several drug-linkers based on oxidized derivatives of the highly potent anthracycline analogue PNU-159682. Resultant ADCs are potent and immunologically specific with linker-dependent bystander activity in co-culture cytotoxicity assays displaying heterogeneous antigen (Ag+/Ag-) expression. Rodent in vivo anti-tumor activity and tolerability are shown with significant differences emerging between the toxicity profile of the cleavable and non-cleavable analogues. In vitro, tumor cells treated with anthracycline ADCs showed key hallmarks of ICD including markers of endoplasmic reticulum (ER) stress and the induction of ICD damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP. In vivo mouse xenograft studies show increased tumoral F4/80+ macrophage infiltration by IHC in anthracycline ADC treated animals relative to controls. ADCs delivering monomethyl auristatin E (MMAE) show comparable activity in ICD assays, confirming MMAE as an ICD inducing ADC payload alongside canonical inducers such as anthracyclines. Our results indicate there is a therapeutic window in rodents alongside ICD induction by anthracycline ADCs, positioning anthracyclines as a potentially impactful class of ADC payloads. Citation Format: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke. Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2013.

A Hierarchical Structured Fiber Device Remodeling the Acidic Tumor Microenvironment for Enhanced Cancer Immunotherapy.

The acidic microenvironment of tumors significantly reduces the anti-tumor effect of immunotherapy. Herein, a hierarchically structured fiber device is developed as a local drug delivery system for remodeling the acidic tumor microenvironment (TME) to improve the therapeutic effect of immunotherapy. Proton pump inhibitors in the fiber matrix can be sustainedly released to inhibit the efflux of intracellular H+ from tumor cells, resulting in the remodeling of the acidic TME. The targeted micelles and M1 macrophage membrane-coated nanoparticles in internal cavities of fiber can induce immunogenic cell death (ICD) of tumor cells and phenotypic transformation of tumor-associated macrophages (TAMs), respectively. The relief of the acidity in the TME further promotes ICD and the polarization of TAMs, alleviating the immunosuppressive microenvironment and synergistically enhancing the antitumor immune response. In vivo results reveal this local drug delivery system restores the pH value of TME from 6.8 to 7.2 and exhibit an excellent immunotherapeutic effect.

Mitochondria-associated ER stress evokes immunogenic cell death through the ROS-PERK-eIF2α pathway under PTT/CDT combined therapy.

Chemodynamic therapy (CDT) can effectively induce immunogenic cell death (ICD) in tumours and is thus a promising strategy for boosting the efficacy of immunotherapy. However, the mechanism by which CDT enhances ICD and lowers ICD efficiency is unknown and this restricts its clinical application. In this study, a second near-infrared (NIR-II) window irradiation-triggered hydrogen peroxide (H2O2) self-supplying nanocomposite ((Cu2Se-CaO2)@LA) was constructed. The modified lauric acid was melted by the heat energy of the NIR-II irradiation, to expose the CaO2 nanoparticles, and they then reacted with water to produce H2O2 and Ca2+. H2O2 was then converted to hydroxyl radicals by the photothermal-enhanced CDT process of the Cu2Se nanocubes. Notably, the CDT and Ca2+ overload was found to induce sequential damage to the mitochondria and endoplasmic reticulum (ER), which upregulated the PERK-mediated eIF2α phosphorylation pathway and caused subsequent ICD. NIR-II irradiation of the (Cu2Se-CaO2)@LA also increased reactive oxygen species (ROS) formation and this was sufficient to increase dendritic cell maturation, attracting cytotoxic T lymphocytes, and suppressing tumour growth in vivo. Overall, we demonstrated that an enhanced CDT strategy under NIR-II exposure and H2O2 self-supply can induce extensive ICD by inducing mitochondria-associated ER stress, which represents a highly effective and promising strategy for ICD amplification and tumour immunotherapy. STATEMENT OF SIGNIFICANCE: In this study, a second near-infrared window (NIR-II) irradiation-triggered and H2O2 self-supplying nanocomposite (named (Cu2Se-CaO2)@LA) was constructed and tested both in vitro and in vivo. These nanoparticles demonstrated promising antitumor activity as designed. Mechanistically, the nanoparticles could damage mitochondria and upregulate the PERK-mediated eIF2αphosphorylation pathway, further causing endoplasmic reticulum stress, and inducing immunogenic cell death through dendritic cell maturation and cytotoxic T lymphocyte recruitment augmented activity. This system represents a highly effective and promising strategy for enhancing tumor immunotherapy and provides new insights for future studies and design refinements.

NIR-II light evokes DNA cross-linking for chemotherapy and immunogenic cell death.

As a DNA damaging agent, oxaliplatin (OXA) can induce immunogenic cell death (ICD) in tumors to activate the immune system. However, the DNA damage induced by OXA is limited and the ICD effect is not strong enough to enhance anti-tumor efficacy. Here, we propose a strategy to maximize the ICD effect of OXA through the mild hyperthermia generated by nanoparticles with a platinum (IV) prodrug of OXA (Pt(IV)-C16) and a near-infrared-II (NIR-II) photothermal agent IR1061 upon the irradiation of NIR-II light. The mild hyperthermia (43°C) holds advantages in two aspects: 1) increase the Pt-DNA cross-linking, leading to enhanced DNA damage and apoptosis; 2) induce stronger ICD effects for cancer immunotherapy. We demonstrated that, compared with OXA and photothermal therapy of IR1061 alone, these nanoparticles under NIR-II light irradiation can significantly improve the anti-cancer efficacy against triple-negative breast cancer 4T1 tumor. This new strategy provides an effective way to improve the therapeutic outcome of OXA. STATEMENT OF SIGNIFICANCE: OXA could induce immunogenic cell death (ICD) via stimulating immune responses by increasing tumor cell stress and death, which triggers tumor-specific immune responses to achieve immunotherapy. However, due to the insufficient Pt-DNA crosslinks, the ICD effect triggered by OXA cannot induce robust immune response. Mild hyperthermia has great potential to maximize the therapeutic outcome of oxaliplatin by increasing the Pt-DNA cross-linking to augment the immunoresponse for enhanced cancer immunotherapy.

NIR responsive nanoenzymes via photothermal ablation and hypoxia reversal to potentiate the STING-dependent innate antitumor immunity

Despite advances in combined photothermal/immunotherapy of tumor, the therapeutic effect has been impaired due to hypoxic microenvironment and inadequate immune activation. Manganese ions directly activated the stimulator of interferon genes (STING) pathway and induced innate antitumor immunity. Herein, a near infrared light (NIR)-responsive nanoenzyme (PB-Mn/OVA NE) was constructed by doping manganese into the ovalbumin (OVA)-templated Prussian blue (PB) nanoparticles. The resultant PB-Mn/OVA NEs exhibited favorable catalase activity to produce oxygen, which was conducive to alleviate the tumor hypoxic microenvironment. Under 808​nm NIR irradiation, the PB-Mn/OVA NEs with outstanding photothermal conversion efficiency of 30% significantly destroyed tumor cells by inducing immunogenic cell death (ICD). Impressively, the PB-Mn/OVA NEs could activate the cGAS-STING pathway to promote the maturation and the antigen cross-presentation ability of dendritic cells (DCs), which further activated cytotoxic T lymphocytes and memory T lymphocytes. Overall, this work presents a powerful nanoenzyme formula to integrate photothermal ablation and hypoxic reversal for triggering robust innate and adaptive antitumor immune response.

Reactive oxygen species-powered cancer immunotherapy: Current status and challenges.

Reactive oxygen species (ROS) are crucial signaling molecules that can arouse immune system. In recent decades, ROS has emerged as a unique therapeutic strategy for malignant tumors as (i) it can not only directly reduce tumor burden but also trigger immune responses by inducing immunogenic cell death (ICD); and (ii) it can be facilely generated and modulated by radiotherapy, photodynamic therapy, sonodynamic therapy and chemodynamic therapy. The anti-tumor immune responses are, however, mostly downplayed by the immunosuppressive signals and dysfunction of effector immune cells within the tumor microenvironment (TME). The past years have seen fierce developments of various strategies to power ROS-based cancer immunotherapy by e.g. combining with immune checkpoints inhibitors, tumor vaccines, and/or immunoadjuvants, which have shown to potently inhibit primary tumors, metastatic tumors, and tumor relapse with limited immune-related adverse effects. In this review, we introduce the concept of ROS-powered cancer immunotherapy, highlight the innovative strategies to boost ROS-based cancer immunotherapy, and discuss the challenges in terms of clinical translation and future perspectives.

The Blockade of Mitogen-Activated Protein Kinase 14 Activation by Marine Natural Product Crassolide Triggers ICD in Tumor Cells and Stimulates Anti-Tumor Immunity

Immunogenic cell death (ICD) refers to a type of cell death that stimulates immune responses. It is characterized by the surface exposure of damage-associated molecular patterns (DAMPs), which can facilitate the uptake of antigens by dendritic cells (DCs) and stimulate DC activation, resulting in T cell immunity. The activation of immune responses through ICD has been proposed as a promising approach for cancer immunotherapy. The marine natural product crassolide, a cembranolide isolated from the Formosan soft coral Lobophytum michaelae, has been shown to have cytotoxic effects on cancer cells. In this study, we investigated the effects of crassolide on the induction of ICD, the expression of immune checkpoint molecules and cell adhesion molecules, as well as tumor growth in a murine 4T1 mammary carcinoma model. Immunofluorescence staining for DAMP ectolocalization, Western blotting for protein expression and Z'-LYTE kinase assay for kinase activity were performed. The results showed that crassolide significantly increased ICD and slightly decreased the expression level of CD24 on the surface of murine mammary carcinoma cells. An orthotopic tumor engraftment of 4T1 carcinoma cells indicated that crassolide-treated tumor cell lysates stimulate anti-tumor immunity against tumor growth. Crassolide was also found to be a blocker of mitogen-activated protein kinase 14 activation. This study highlights the immunotherapeutic effects of crassolide on the activation of anticancer immune responses and suggests the potential clinical use of crassolide as a novel treatment for breast cancer.

Anthelmintic Drugs as Emerging Immune Modulators in Cancer.

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.

Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy.

Malignant pleural mesothelioma (MPM) is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options. For MPM patients, the effectiveness of immunotherapy may be influenced by damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy. The RNA-seq of 397 patients (263 patients with clinical data, 57.2% male, 73.0% over 60 yrs.) were gathered from eight public datasets as a training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis. Three validation cohorts of patients or murine were established from TCGA and GEO databases. Comparisons were made across each subtype's immune status, gene mutations, survival prognosis, and predicted response to therapy. Based on the DAMPs gene expression, MPMs were categorized into two subtypes: the nuclear DAMPs subtype, which is classified by the upregulation of immune-suppressed pathways, and the inflammatory DAMPs subtype, which is distinguished by the enrichment of proinflammatory cytokine signaling. The inflammatory DAMPs subgroup had a better prognosis, while the nuclear DAMPs subgroup exhibited a worse outcome. In validation cohorts, the subtyping system was effectively verified. We further identified the genetic differences between the two DAMPs subtypes. It was projected that the inflammatory DAMPs subtype will respond to immunotherapy more favorably, suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy. We constructed a subtyping model based on ICD-associated DAMPs in MPM, which might serve as a signature to gauge the outcomes of immune checkpoint blockades. Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM.

Type I interferon signaling in malignant blasts contributes to treatment efficacy in AML patients

While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor 3 (TLR3)-dependent mechanism that is not driven by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms elicited by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling was found to have independent prognostic value on relapse-free survival and overall survival in a cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.

Definition of a Novel Immunogenic Cell Death-Relevant Gene Signature Associated with Immune Landscape in Gastric Cancer.

Immunogenic cell death (ICD) induces anti-tumor immunity and aids in dismantling the immunosuppressive immune microenvironment (TME), which belongs to a type of regulated cell death. The differentiation of gastric cancer (GC) subtypes and the discovery of prognostic biomarkers are crucial for its treatment because GC is a disease that is both highly heterogeneous and aggressive. However, although the induction of ICD in tumor cells is associated with afavorableprognosis, the exact mechanism of its role in GC remains unclear. Transcriptome profiling data and clinical data of GC patients were retrieved from The Cancer Genome Atlas (TCGA) database. Herein, patients were classified with the consensus clustering algorithm, and the associated biological functions and immune microenvironment infiltration were explored based on the expression of ICD-associated genes. A risk score signature consisting of 11 ICD-related genes was established via the least absolute shrinkage and selection operator regression (LASSO) method. We have retrieved similar studies in recent years and compared them with our study using the time-dependent receiver operating characteristic (ROC) curves. Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA) were performed to explore the association between the signature and tumor microenvironment (TME). Two distinct subtypes associated with ICD in GC were identified, each with a different prognosis. The ICD-high expression subtype was associated with higher immune cell infiltration and a better prognosis. The ICD-related gene signature containing 11 genes (CGB5, Z84468.1, APOA5, EPHA8, CLEC18C, TLR7, MUC7, MUC15, CTLA4, CALB2, and UGT2B28), could independently and accurately predict the prognosis of GC. In this study, an ICD-based classification was conducted to assist in the diagnosis and personalized therapy for GC. The ICD-related genes risk score model was established to predict prognosis.

An anisotropic photocatalytic agent elicits robust photoimmunotherapy through plasmonic catalysis-mediated tumor microenvironment modulation

Photoimmunotherapy, which not only directly kills tumor cells but also elicits antitumor immune responses by inducing immunogenic cell death (ICD), has emerged as a promising approach for cancer treatment. However, the hypoxic immunosuppressive tumor microenvironment (TME) with limited immune response immensely compromises the therapeutic outcomes. Herein, an end-deposited plasmonic catalyst (GCNRs) is developed by selectively depositing semiconducting ceria nanosheets onto the two ends of gold nanorods for plasmonic catalysis-mediated TME modulation. Specially, an efficient low-power near-infrared-triggered electron-hole spatial separation along the longitudinal axis of GCNRs occurs due to the end-deposition morphology. The generated hot electrons and hot holes separately participate in the reactive oxygen species (ROS) generation and oxygen-evolution half-reaction, thereby modulating the immunosuppressive TME via concurrent ROS-mediated ICD-induction and H2O2-independent hypoxia relief. Unprecedentedly, mere injection of GCNRs can induce significant infiltration of cytotoxic T cells into tumor tissues, significantly inhibiting the growth and metastasis of tumors. Our study represents a promising plasmonic catalysis-mediated TME modulation strategy in phototherapy-based immuno-oncology.

Tailor-Made Autophagy Cascade Amplification Polymeric Nanoparticles for Enhanced Tumor Immunotherapy.

Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol-polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.

SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate——G1T48 (NCT03455270), with a TrxR inhibitor——N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.

Immunogenic cell death in cancer immunotherapy

Cancer immunotherapy has been acknowledged as a new paradigm for cancer treatment, with notable therapeutic effects on certain cancer types. Despite their significant potential, clinical studies over the past decade have revealed that cancer immunotherapy has low response rates in the majority of solid tumors. One of the key causes for poor responses is known to be the relatively low immunogenicity of solid tumors. Because most solid tumors are immune desert 'cold tumors' with antitumor immunity blocked from the onset of innate immunity, combination therapies that combine validated T-based therapies with approaches that can increase tumor-immunogenicity are being considered as relevant therapeutic options. This review paper focuses on immunogenic cell death (ICD) as a way of enhancing immunogenicity in tumor tissues. We will thoroughly review how ICDs such as necroptosis, pyroptosis, and ferroptosis can improve anti-tumor immunity and outline clinical trials targeting ICD. Finally, we will discuss the potential of ICD inducers as an adjuvant for cancer immunotherapy.

Immunogenic Cell Death Photothermally Mediated by Erythrocyte Membrane-Coated Magnetofluorescent Nanocarriers Improves Survival in Sarcoma Model.

Inducing immunogenic cell death (ICD) during cancer therapy is a major challenge that might significantly improve patient survival. The purpose of this study was to develop a theranostic nanocarrier, capable both of conveying a cytotoxic thermal dose when mediating photothermal therapy (PTT) after its intravenous delivery, and of consequently inducing ICD, improving survival. The nanocarrier consists of red blood cell membranes (RBCm) embedding the near-infrared dye IR-780 (IR) and camouflaging Mn-ferrite nanoparticles (RBCm-IR-Mn). The RBCm-IR-Mn nanocarriers were characterized by size, morphology, surface charge, magnetic, photophysical, and photothermal properties. Their photothermal conversion efficiency was found to be size- and concentration-dependent. Late apoptosis was observed as the cell death mechanism for PTT. Calreticulin and HMGB1 protein levels increased for in vitro PTT with temperature around 55 °C (ablative regime) but not for 44 °C (hyperthermia), suggesting ICD elicitation under ablation. RBCm-IR-Mn were then intravenously administered in sarcoma S180-bearing Swiss mice, and in vivo ablative PTT was performed five days later. Tumor volumes were monitored for the subsequent 120 days. RBCm-IR-Mn-mediated PTT promoted tumor regression in 11/12 animals, with an overall survival rate of 85% (11/13). Our results demonstrate that the RBCm-IR-Mn nanocarriers are great candidates for PTT-induced cancer immunotherapy.