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Abstract Background Gliomas are highly refractory intracranial cancers characterized by genetic and transcriptional heterogeneity. However, therapeutic options are limited. In the last years, copper‐induced cell death is becoming a prospective treatment strategy for gliomas and other solid tumors, but copper metabolism‐related genes associated with cancer development remain unclear. Methods We first collected gene expression data from The Cancer Genome Atlas (TCGA) to identify significantly differentially expressed copper metabolism‐related genes in gliomas. Using these genes, we performed COX regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression to construct the prognostic model. The prognostic value of the model was further validated by CGGA testing set. Subsequently, functional analyses were carried out, including gene set enrichment analysis (GSEA), immune infiltration analysis, and mutation analysis. Finally, the expression levels of these genes were verified by immunohistochemical analysis. Results The prognostic model consisted of 7 genes: CDK1, LOXL2, LOXL3, NFE2L2, SLC31A1, SUMF1 and FDX1. According to this prognosis model, glioma patients could be split into the high‐risk group or low‐risk group, and the low‐risk group showed significantly better prognostic survival (p

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.

Immune checkpoint inhibitors (ICIs) are an expanding class of immunotherapeutic agents with the potential to cure cancer. Despite the outstanding clinical response in patient subsets, most individuals become refractory or develop resistance. Patient stratification and personalized immunotherapies are limited by the absence of predictive response markers. Recent findings show that dominant patterns of immune cell composition, T-cell status and heterogeneity, and spatiotemporal distribution of immune cells within the tumor microenvironment (TME) are becoming essential determinants of prognosis and therapeutic response. In this context, ICIs also function as investigational tools and proof of concept, allowing the validation of the identified mechanisms. After reviewing the current state of ICIs, this article will explore new comprehensive predictive markers for ICIs based on recent discoveries. We will discuss the recent establishment of a classification of TMEs into immune archetypes as a tool for personalized immune profiling, allowing patient stratification before ICI treatment. We will discuss the developing comprehension of T-cell diversity and its role in shaping the immune profile of patients. We describe the potential of strategies that score the mutual spatiotemporal modulation between T-cells and other cellular components of the TME. Additionally, we will provide an overview of a range of synthetic and naturally occurring or derived small molecules. We will compare compounds that were recently identified by in silico prediction to wet lab-validated drug candidates with the potential to function as ICIs and/or modulators of the cellular components of the TME.

Imbalanced immune homeostasis in cancer microenvironment is a hallmark of cancer. Increasing evidence demonstrated that long non-coding RNAs (lncRNAs) have emerged as key regulatory molecules in directly blocking the cancer immunity cycle, apart from activating negative regulatory pathways for restraining tumor immunity. lncRNAs reshape the tumor microenvironment via the recruitment and activation of innate and adaptive lymphoid cells. In this review, we summarized the versatile mechanisms of lncRNAs implicated in cancer immunity cycle, including the inhibition of antitumor T cell activation, blockade of effector T cell recruitment, disruption of T cell homing, recruitment of immunosuppressive cells, and inducing an imbalance between antitumor effector cells (cytotoxic T lymphocytes, M1 macrophages, and T helper type 1 cells) versus immunosuppressive cells (M2 macrophages, T helper type 2 cells, myeloid derived suppressor cells, and regulatory T cells) that infiltrate in the tumor. As such, we would highlight the potential of lncRNAs as novel targets for immunotherapy. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia represents a malignant proliferation of lymphoid cells blocked at an early stage of cell differentiation. It is the most common cancer occurring in children. Despite favorable prognosis, the survival rate of patients with poor treatment response or relapse remains dismal. The interaction between leukemic cells and the tumor immune microenvironment is pivotal in mediating tumor progression. In this study we evaluated associations between Treg and Th17 lymphocytes and the clinical presentation of ALL pediatric patients to validate their value in monitoring treatment outcome. The peripheral blood and bone marrow aspirates from 35 pediatric patients with ALL and 48 healthy control subjects were selected for the experiment. We demonstrated the numbers of Th17 lymphocytes and Tregs were increased in the bone marrow of ALL patients at the moment of diagnosis compared to the healthy control group, with the latter significantly decreasing during the course of ALL treatment. Patients with lower Th17 were found to demonstrate higher risk of blasts prevalence in bone marrow at day 33. ALL patients with lower WBC demonstrated higher frequency of Tregs. In summary, we identified a significant role of Th17 and Treg lymphocytes in ALL of pediatric patients and their contribution to disease-related parameters. [ABSTRACT FROM AUTHOR]

Cancer cells circumvent immune surveillance via diverse strategies. In accordance, a large number of complex studies of the immune system focusing on tumor cell recognition have revealed new insights and strategies developed, largely through major histocompatibility complexes (MHCs). As one of them, tumor-specific MHC-II expression (tsMHC-II) can facilitate immune surveillance to detect tumor antigens, and thereby has been used in immunotherapy, including superior cancer prognosis, clinical sensitivity to immune checkpoint inhibition (ICI) therapy and tumor-bearing rejection in mice. NK cells play a unique role in enhancing innate immune responses, accounting for part of the response including immunosurveillance and immunoregulation. NK cells are also capable of initiating the response of the adaptive immune system to cancer immunotherapy independent of cytotoxic T cells, clearly demonstrating a link between NK cell function and the efficacy of cancer immunotherapies. Eosinophils were shown to feature pleiotropic activities against a variety of solid tumor types, including direct interactions with tumor cells, and accessorily affect immunotherapeutic response through intricating cross-talk with lymphocytes. Additionally, microbial sequencing and reconstitution revealed that commensal microbiota might be involved in the modulation of cancer progression, including positive and negative regulatory bacteria. They may play functional roles in not only mucosal modulation, but also systemic immune responses. Here, we present a panorama of the cancer immune network mediated by MHCI/II molecules, immune cells and commensal microbiota and a discussion of prospective relevant intervening mechanisms involved in cancer immunotherapies. [ABSTRACT FROM AUTHOR]

RNA modification plays an important role in epigenetics at the posttranscriptional level, and 5-methylcytosine (m5C) has attracted increasing attention in recent years due to the improvement in RNA m5C site detection methods. By influencing transcription, transportation and translation, m5C modification of mRNA, tRNA, rRNA, lncRNA and other RNAs has been proven to affect gene expression and metabolism and is associated with a wide range of diseases, including malignant cancers. RNA m5C modifications also substantially impact the tumor microenvironment (TME) by targeting different groups of immune cells, including B cells, T cells, macrophages, granulocytes, NK cells, dendritic cells and mast cells. Alterations in immune cell expression, infiltration and activation are highly linked to tumor malignancy and patient prognosis. This review provides a novel and holistic examination of m5C-mediated cancer development by examining the exact mechanisms underlying the oncogenicity of m5C RNA modification and summarizing the biological effects of m5C RNA modification on tumor cells as well as immune cells. Understanding methylationrelated tumorigenesis can provide useful insights for the diagnosis as well as the treatment of cancer. [ABSTRACT FROM AUTHOR]

Introduction: Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). Methods: In this study, we separately investigated the differentiation of CD8+ regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing de-novo NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigenunexperienced CCR7+CD45RA+CD31+ recent thymic emigrant (RTE) cells differentiate via CD45RA-CD31+ memory (CD31+ memory) cells, via resting mature naïve (MN) cells or via direct proliferation into CD45RA-CD31-memory (CD31-memory) cells, consisting of both CCR7+CD45RA-central memory (CM) and CCR7-CD45RA-effector memory (EM) cells. Results: We found that both RTE Treg and Tresp differentiation via CD31+ memory Tregs/Tresps was age-independently increased in KTR, who developed de novo NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8+ Treg/Tresp ratio, suggesting this ratio as a reliable marker for denovo NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained via conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. Discussion: In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8+ Tregs more than that of CD8+ Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR. [ABSTRACT FROM AUTHOR]

Abstract T cells are a group of lymphocytes that play a central role in the immune system, notably, eliminating pathogens and attacking cancer while being tolerant of the self. Elucidating how immune tolerance is ensured has become a significant research issue for understanding the pathogenesis of autoimmune diseases as well as cancer immunity. T cell immune tolerance is established mainly in the thymic medulla by the removal of self-responsive T cells and the generation of regulatory T cells, this process depends mainly on the expression of a variety of tissue restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs). The expression of TRAs is known to be regulated by at least two independent factors, Fezf2 and Aire, which play non-redundant and complementary roles by different mechanisms. In this review, we introduce the molecular logic of thymic self-antigen expression that underlies T cell selection for the prevention of autoimmunity and the establishment of immune surveillance.

The development of immunotherapy, especially immune-checkpoint inhibitors targeting PD-1/PD-L1, has improved the outcomes of patients with esophageal cancer. However, not all population derives benefit from the agents. Recently, kinds of biomarkers were introduced to predict the response to immunotherapy. However, the effects of these reported biomarkers are controversial and many challenges remain. In this review, we aim to summarize the current clinical evidence and provide a comprehensive understanding of the reported biomarkers. We also discuss the limits of the present biomarkers and propose our own opinions on which viewers’ discretion are advised. [ABSTRACT FROM AUTHOR]

Background: Gliomas are highly refractory intracranial cancers characterized by genetic and transcriptional heterogeneity. However, therapeutic options are limited. In the last years, copper‐induced cell death is becoming a prospective treatment strategy for gliomas and other solid tumors, but copper metabolism‐related genes associated with cancer development remain unclear. Methods: We first collected gene expression data from The Cancer Genome Atlas (TCGA) to identify significantly differentially expressed copper metabolism‐related genes in gliomas. Using these genes, we performed COX regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression to construct the prognostic model. The prognostic value of the model was further validated by CGGA testing set. Subsequently, functional analyses were carried out, including gene set enrichment analysis (GSEA), immune infiltration analysis, and mutation analysis. Finally, the expression levels of these genes were verified by immunohistochemical analysis. Results: The prognostic model consisted of 7 genes: CDK1, LOXL2, LOXL3, NFE2L2, SLC31A1, SUMF1 and FDX1. According to this prognosis model, glioma patients could be split into the high‐risk group or low‐risk group, and the low‐risk group showed significantly better prognostic survival (p < 0.001). Moreover, the high‐risk group had higher levels of immune cell infiltration, immune checkpoint genes expression, and higher tumor mutational burden (TMB), which indicates that they might benefit more from immunotherapy. Finally, we confirmed the expression level of FDX1, SUMF1, and SLC31A1 protein as significantly different in glioblastoma, lower‐grade glioma, and non‐tumor brain tissues by immunohistochemical analysis, and the high expression of FDX1 and SLC31A1 protein was related to poor survival in glioma patients. Conclusions: Our study could contribute to the prognosis prediction and decision‐making in patients with gliomas. [ABSTRACT FROM AUTHOR]

BackgroundN6-methyladenosine (m6A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m6A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m6A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive.MethodsDifferentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m6A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation.ResultsThe m6A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration.ConclusionThe m6A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies.

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented by immune checkpoint blocking has increasingly become an effective cancer treatment, and increasing shreds of evidence show that m6A RNA methylation affects cancer immunity in various cancers. Until now, there have been few reviews about the role and mechanism of m6A modification in cancer immunity. Here, we first summarized the regulation of m6A regulators on the expression of target messenger RNAs (mRNA) and their corresponding roles in inflammation, immunity response, immune process and immunotherapy in various cancer cells. Meanwhile, we described the roles and mechanisms of m6A RNA modification in tumor microenvironment and immune response by affecting the stability of non-coding RNA (ncRNA). Moreover, we also discussed the m6A regulators or its target RNAs which might be used as predictor of cancer diagnosis and prognosis, and shed light on the potentiality of m6A methylation regulators as therapeutic targets in cancer immunity.

The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs. As a result of this systematic review, we have stratified the miRNA landscape into (i) miRNAs whose levels directly modulate response to ICIs, (ii) miRNAs whose expression is modulated by ICIs, and (iii) miRNAs that directly elicit toxic effects or participate in immune-related adverse events (irAEs) caused by ICIs.

Abstract Background Nasopharyngeal carcinoma (NPC) is a geographically and racially variable disease that has a high incidence in Southeast China. According to previous studies on tumor immunity, we compared multiple clinical parameters and blood indexes with outcomes regarding to Epstein-Barr virus (EBV) status in NPC patients. Methods According to the EBV load at diagnosis, 220 NPC patients who received concurrent chemoradiotherapy (CRT) were divided into two groups: EBV DNA ≥ 1500 copies/mL and EBV DNA

RNA modification plays an important role in epigenetics at the posttranscriptional level, and 5-methylcytosine (m5C) has attracted increasing attention in recent years due to the improvement in RNA m5C site detection methods. By influencing transcription, transportation and translation, m5C modification of mRNA, tRNA, rRNA, lncRNA and other RNAs has been proven to affect gene expression and metabolism and is associated with a wide range of diseases, including malignant cancers. RNA m5C modifications also substantially impact the tumor microenvironment (TME) by targeting different groups of immune cells, including B cells, T cells, macrophages, granulocytes, NK cells, dendritic cells and mast cells. Alterations in immune cell expression, infiltration and activation are highly linked to tumor malignancy and patient prognosis. This review provides a novel and holistic examination of m5C-mediated cancer development by examining the exact mechanisms underlying the oncogenicity of m5C RNA modification and summarizing the biological effects of m5C RNA modification on tumor cells as well as immune cells. Understanding methylation-related tumorigenesis can provide useful insights for the diagnosis as well as the treatment of cancer.

Simple Summary: Many non-coding RNAs are deregulated in cancer. In one of the most intriguing of their various roles, they control immune regulatory proteins, allowing tumor cells to evade the body's own defenses. In this work, we describe the mechanisms by which certain ncRNAs help tumor cells escape the immune response. In-depth insight into these mechanisms is required to further develop therapeutic strategies targeting immune checkpoints and improve the performance of cancer immunotherapy. In recent years, cancer treatment has undergone significant changes, predominantly in the shift towards immunotherapeutic strategies using immune checkpoint inhibitors. Despite the clinical efficacy of many of these inhibitors, the overall response rate remains modest, and immunotherapies for many cancers have proved ineffective, highlighting the importance of knowing the tumor microenvironment and heterogeneity of each malignancy in patients. Long non-coding RNAs (lncRNAs) have attracted increasing attention for their ability to control various biological processes by targeting different molecular pathways. Some lncRNAs have a regulatory role in immune checkpoints, suggesting they might be utilized as a target for immune checkpoint treatment. The focus of this review is to describe relevant lncRNAs and their targets and functions to understand key regulatory mechanisms that may contribute in regulating immune checkpoints. We also provide the state of the art on super-enhancers lncRNAs (selncRNAs) and circular RNAs (circRNAs), which have recently been reported as modulators of immune checkpoint molecules within the framework of human cancer. Other feasible mechanisms of interaction between lncRNAs and immune checkpoints are also reported, along with the use of miRNAs and circRNAs, in generating new tumor immune microenvironments, which can further help avoid tumor evasion. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor cell-derived extracellular vesicles (TEVs) are an important means of tumor communication with, and manipulation of, the patient's physiology. TEVs influence the local tumor environment as well as the systemic conditions of the patient. Progressive changes in tumor interactions with the host immune system are defined as "immunoediting". Here, we summarize TEV effects on the immune system during the stages of cancer immunoediting and outline the molecular and cellular characteristics of interactions that result in complete tumor regression versus tumor immune escape and progression. Generally, the cargo profile of TEVs naturally changes during immunoediting toward immunosuppression while different cell stress or treatment conditions can inhibit this process or even reverse it to immunostimulation by altering the TEVs cargos. Therefore, understanding potential immunotherapeutic properties and how they can be manipulated to treat cancer should be considered a new research approach in oncoimmunotherapy. The tumor microenvironment (TME) within and around a tumor is a complex interacting mixture of tumor cells with various stromal cells, including endothelial cells, fibroblasts, and immune cells. In the early steps of tumor formation, the local microenvironment tends to oppose carcinogenesis, while with cancer progression, the microenvironment skews into a protumoral TME and the tumor influences stromal cells to provide tumor-supporting functions. The creation and development of cancer are dependent on escape from immune recognition predominantly by influencing stromal cells, particularly immune cells, to suppress antitumor immunity. This overall process is generally called immunoediting and has been categorized into three phases; elimination, equilibrium, and escape. Interaction of tumor cells with stromal cells in the TME is mediated generally by cell-to-cell contact, cytokines, growth factors, and extracellular vesicles (EVs). The least well studied are EVs (especially exosomes), which are nanoparticle-sized bilayer membrane vesicles released by many cell types that participate in cell/cell communication. EVs carry various proteins, nucleic acids, lipids, and small molecules that influence cells that ingest the EVs. Tumor-derived extracellular vesicles (TEVs) play a significant role in every stage of immunoediting, and their cargoes change from immune-activating in the early stages of immunoediting into immunosuppressing in the escape phase. In addition, their cargos change with different treatments or stress conditions and can be influenced to be more immune stimulatory against cancer. This review focuses on the emerging understanding of how TEVs affect the differentiation and effector functions of stromal cells and their role in immunoediting, from the early stages of immunoediting to immune escape. Consideration of how TEVs can be therapeutically utilized includes different treatments that can modify TEV to support cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug therapy is an important treatment for cancer patients; however, drug resistance severely affects the survival time and quality of life of cancer patients. Oxidative phosphorylation (OXHPOS) is an important metabolic process in cells that drives cancer drug resistance and exerts a significant influence on responses to anticancer therapy. Targeting OXPHOS can specifically eliminate cancer stem cells and delay the acquisition of drug resistance. Hence, OXPHOS has become a novel pharmacological target in cancer treatment. OXPHOS inhibitors in combination with conventional therapies have significantly increased the efficacy of treatments and attenuated resistance to anticancer drugs. Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer therapy in certain cancers, such as melanomas, lymphomas, colon cancers, leukemias and pancreatic ductal adenocarcinoma (PDAC). However, the effect of OXPHOS on cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME). Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to cancer therapy. Resistant cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in cancer cells, mitochondrial OXPHOS is significantly downregulated in tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on cancer drug resistance, thereby explaining how this metabolic process plays a dual role in cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in cancer cells, as it is vital for discovering new drug targets. [ABSTRACT FROM AUTHOR]

Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of ovarian and other types of cancers. In this study we show that SV.IL-12 combined with an agonistic OX40 antibody can eliminate ovarian cancer in a Mouse Ovarian Surface Epithelial Cell Line (MOSEC) model and further prevent tumors in mice rechallenged with tumor cells after approximately 5 months. Treatment efficacy is shown to be dependent upon T-cells that are transcriptionally and metabolically reprogramed. An influx of immune cells to the tumor microenvironment occurs. Combination of sequences encoding both IL-12 and anti-OX40 into a single SV vector, SV.IgGOX40.IL-12, facilitates the local delivery of immunoregulatory agents to tumors enhancing the anti-tumor response. We promote SV.IgGOX40.IL-12 as a safe and effective therapy for multiple types of cancer. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA)-based gene therapy is a robust approach to treating human cancers. However, the low target specificity and safety issues associated with viral vectors have limited the clinical use of miRNA therapeutics. In the present study, we aimed to develop a biocompatible nanocarrier to deliver the tumor suppressor miR-30a-5p for gene therapy of ocular melanoma. The quasi-mesoporous magnetic nanospheres (MMNs) were prepared by polyelectrolytes-mediated self-assembling Fe 3 O 4 nanocrystals; the cationic polymer capped quasi-mesoporous inner tunnels of the MMNs facilitate high miRNA loading and protect from nuclease degradation. Then, the outer layer of the MMNs was modified with a disulfide bond bridged very low molecular weight polyethyleneimine (PEI) network to form redox-responsive nanospheres (rMMNs) that enhance the miRNA payload and enable miRNA release under glutathione-dominant tumor microenvironment. The miR-30a-5p loaded rMMNs nanodrug (miR-30a-5p@rMMNs) upregulated miR-30a-5p level and inhibited malignant phenotypes of ocular melanoma by targeting the transcription factor E2F7 both in vitro and in vivo. Additionally, rMMNs act as an enhancer to increase cancer cell apoptosis by modulating M1-like macrophage polarization and activating Fenton reaction. Thus, the rMMNs is a promising miRNA carrier for gene therapy and could enhance pro-inflammatory immunity in melanoma and other cancers. • miR-30a-5p@rMMNs inhibited malignant phenotypes of ocular melanoma both in vitro and in vivo. • The rMMNs promoted M1 macrophage polarization thus synergistically enhancing pro-inflammatory anti-tumor immunity against melanoma. • The rMMNs showed no obvious toxicity under the injection dose. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Cancer immunoediting is crucial to understand the success or failure of a tumor. Immune system plays dual roles in tumor development and progression, promoting or suppressing tumor depending on tumor microenvironment and the events that lead to initiation of carcinogenesis. The immune system has potential to recognize and destroy tumors, and thus function as a primary defense mechanism against cancer. On the other hand, unresolved immune responses can result in the growth and progression of cancer. Objectives: The host immune system determines tumour fate in three phases (Elimination, Equilibrium and Escape) and according to this theory, it blocks adaptive and innate tumour responses or promotes conditions that favour tumour progression. Conclusion: The purpose of this review is to emphasise the importance of immunity in tumour promotion and suppression. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are essential for antitumor T-cell responses to immune checkpoint inhibitor therapies. We have previously reported that the secreted protein neudesin suppresses DC function. In contrast, neudesin has been found to be abundantly expressed in human cancers. In this study, we evaluated the role of neudesin in cancer immunity. Cancer-related database analysis revealed that patients with melanoma with low neudesin expression exhibited increased infiltration of DCs and CD8+ T cells and improved outcomes of checkpoint inhibitor therapy. In mouse tumor models, neudesin deficiency delayed tumor growth and increased the proportions of Type 1 conventional DCs (cDC1s) and tumor antigen-specific CD8+ T cells in tumors and tumor-infiltrating lymph nodes. Neudesin -deficient antitumor cDC1 vaccine enhanced the systemic immunity more effectively than the wild-type cDC1 vaccine. Overall, our findings highlight the importance of neudesin in cancer immunity, providing a novel target for immunotherapy. • Low neudesin expression is associated with a good prognosis in patients with cancer. • Neudesin deficiency inhibits tumor growth in mouse models. • Neudesin deficiency elevates cDC1-induced tumor antigen-specific CD8+ T cell number. • Neudesin-deficient cDC1 cancer vaccines promote systemic CD8+ T cell responses. [ABSTRACT FROM AUTHOR]

• S. glabra significantly inhibits the proliferation of lung cancer cells by inducing ferroptosis. • S. glabra induces ferroptosis in lung cancer cells through the activation of HMOX1 and the inhibition of GPX4. • S. glabra enhances the levels of anti-tumor immune cells, including t cells and natural killer (NK) cells, as well as cytokines such as interleukin-2 (IL-2). Sarcandra glabra (S. glabra), a traditional Chinese medicine (TCM), has demonstrated significant anticancer activity; however, the underlying mechanisms have not yet been fully elucidated. This study aimed to investigate the effects of S. glabra on lung cancer and to explore its underlying mechanisms. The chemical profile of S. glabra was analyzed via ultrahigh-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). The effects of S. glabra on the viability, proliferation, apoptosis, migration, and invasion of lung cancer cells were assessed via CCK8, colony formation, flow cytometry, scratch, and Transwell assays. In vivo anticancer activity was evaluated in an LLC mouse model. Proteomic analysis was performed to identify key molecules and pathways in S. glabra -treated LLC cells. The expression of ferroptotic proteins and associated cellular events were examined via western blotting, ROS production, iron accumulation, and lipid peroxidation assays. Immune modulation in tumor-bearing mice was evaluated by detecting immune cells and cytokines in the peripheral blood and tumor tissue. Our analysis quantified 1997 chemical markers in S. glabra aqueous extracts. S. glabra inhibited the viability and proliferation of lung cancer cells and induced cell cycle arrest and apoptosis. Scratch and Transwell assays demonstrated that S. glabra suppressed the migration and invasion of lung cancer cells. Oral administration of S. glabra significantly inhibited tumor growth in LLC tumor-bearing mice. Proteomic analysis revealed that S. glabra upregulated the expression of the HMOX1 protein and activated the ferroptosis pathway. Consistent with these findings, we found that S. glabra triggered ferroptosis in lung cancer cells, as evidenced by the upregulation of HMOX1, downregulation of GPX4 and ferritin light chain proteins, iron accumulation, increased ROS production, and lipid peroxidation. Furthermore, S. glabra demonstrated immunostimulatory properties in LLC tumor-bearing mice, leading to increased populations of immune cells (NK cells) and elevated cytokine levels (IL-2). This study is the first to demonstrate that S. glabra induces ferroptosis in lung cancer cells by regulating HMOX1, GPX4, and FTL. These findings provide a robust scientific basis for the clinical application of S. glabra in lung cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma. [Display omitted] • TAMs recycle cholesterol-rich myelin, acquiring lipid-laden features in glioblastoma • Epigenetic rewiring induced by myelin debris scavenging underlies LLM immunosuppressive features • LLMs transfer myelin-derived lipids to glioblastoma cells to fuel disease progression • LLMs correlate with aggressive mesenchymal subtype and poor prognosis in patients Recycling of cholesterol-rich myelin debris by macrophages leads to the emergence of lipid-laden macrophages (LLMs) in glioblastoma. LLMs support glioblastoma malignancy through transfer of myelin-derived lipids to tumor cells, fueling cancer cell proliferation and recurrence. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.

Breast cancers regroup many heterogeneous diseases unevenly responding to currently available therapies. Approximately 70–80% of breast cancers express hormone (estrogen or progesterone) receptors. Patients with these hormone-dependent breast malignancies benefit from therapies targeting endocrine pathways. Nevertheless, metastatic disease remains a major challenge despite available treatments, and relapses frequently ensue. By improving patient survival and quality of life, cancer immunotherapies have sparked considerable enthusiasm and hope in the last decade but have led to only limited success in breast cancers. In addition, only patients with hormone-independent breast cancers seem to benefit from these immune-based approaches. The present review examines and discusses the current literature related to the role of hormone receptor signaling (specifically, an estrogen receptor) and the impact of its modulation on the sensitivity of breast cancer cells to the effector mechanisms of anti-tumor immune responses and on the capability of breast cancers to escape from protective anti-cancer immunity. Future research prospects related to the possibility of promoting the efficacy of immune-based interventions using hormone therapy agents are considered.

Abstract Actinidia chinensis Planch. root extract (acRoots) is a famous Chinese traditional medicine used in the treatment of a variety of diseases, such as tumours and cardiovascular diseases, etc. However, its therapeutic mechanisms remain unclear. In this review, the biological features of acRoots and its chemical compositions are explored, including polysaccharides, triterpenes, phenols, flavonoids and so on. The pathogenesis of cancer involves not only genetic factors but also the microenvironment. Different types of immune cells, such as T cells, macrophages and neutrophils, play an essential role in cancer development, and acRoots was found to take part in modulating cancer immunity. Therefore, this article summarises its role in cancer immunity and unmasks the potential underlying mechanisms by incorporating our research on cancer immunity.

With the constantly deeper understanding of individualized precision therapy, immunotherapy is increasingly developed and personalized. The tumor immune microenvironment (TIME) mainly consists of infiltrating immune cells, neuroendocrine cells, extracellular matrix, lymphatic vessel network, etc. It is the internal environment basis for the survival and development of tumor cells. As a characteristic treatment of traditional Chinese medicine, acupuncture has shown potentially beneficial impacts on TIME. The currently available information demonstrated that acupuncture could regulate the state of immunosuppression through a range of pathways. An effective way to understand the mechanisms of action of acupuncture was to analyze the response following treatment of the immune system. This research reviewed the mechanisms of acupuncture regulating tumor immunological status based on innate and adaptive immunity.

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57-70, 67; Cell 144:646-674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823-837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.

Macrophages of the M2 phenotype in malignant tumors significantly aid tumor progression and metastasis, as opposed to the M1 phenotype that exhibits anti-cancer characteristics. Raising the ratio of M1/M2 is thus a promising strategy to ameliorate the tumor immunomicroenvironment toward cancer inhibition. We report here that tumor necrosis factor superfamily-15 (TNFSF15), a cytokine with anti-angiogenic activities, is able to facilitate the differentiation and polarization of macrophages toward M1 phenotype. We found that tumors formed in mice by Lewis lung carcinoma (LLC) cells artificially overexpressing TNFSF15 exhibited retarded growth. The tumors displayed a greater percentage of M1 macrophages than those formed by mock-transfected LLC cells. Treatment of mouse macrophage RAW264.7 cells with recombinant TNFSF15 led to augmentation of the phagocytic and pro-apoptotic capacity of the macrophages against cancer cells. Mechanistically, TNFSF15 activated STAT1/3 in bone marrow cells and MAPK, Akt and STAT1/3 in naive macrophages. Additionally, TNFSF15 activated STAT1/3 but inactivated STAT6 in M2 macrophages. Modulations of these signals gave rise to a reposition of macrophage phenotypes toward M1. The ability of TNFSF15 to promote macrophage differentiation and polarization toward M1 suggests that this unique cytokine may have a utility in the reconstruction of the immunomicroenvironment in favor of tumor suppression.

Cancer is an evolutionary disease. Intra-tumor heterogeneity (ITH), which describes the diversity within individual tumors, sets the foundation for evolution. The fitness of tumor cells is determined by their microenvironment, which exerts intense selection pressure that generally favors cells with survival and proliferation advantages. It has been revealed that host immunity dramatically influences the evolutionary trajectory of cancer. As technologies advance, a refined map of the immune system's involvement in cancer evolution has gradually come to our knowledge. Here we specifically view cancer through the lens of evolutionary immunological biology. We will cover the neoplastic evolution under immunosurveillance, including how the host immunity shapes the tumor evolutionary trajectory and how progressive tumors modulate the host immunity to survive. A comprehensive understanding of the interplay between cancer evolution and cancer immunity provides clues to combating cancer strategically. • Cancer is an evolutionary process, and the immune system poses intense selection pressure on cancer progression. • Intra-tumor heterogeneity (ITH) is the main substrate for clonal evolution, and influences cancer evolutionary mechanisms. • Host immunity drives cancer progression in the form of inflammation, and shapes cancer evolution through immunoediting. • Cancer develops mechanisms to evade immunosurveillance, generating a severely compromised host immunity. [ABSTRACT FROM AUTHOR]

Background: Disorders of CD274 and PDCD1LG2 contribute to immune escape in human cancers, and treatment with anti-programmed death receptor 1 (PD-1) has been widely used in recurrent or metastatic tumors. However, integrated studies considering CD274 and PDCD1LG2 across cancers remain limited. Materials and Methods: Differences in expression levels of CD274 and PDCD1LG2 were analyzed in diverse cancer types using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The clinical information and matched expression profiles of TCGA patients were obtained to determine the prognostic value of CD274 and PDCD1LG2. Moreover, correlations between CD274 and PDCD1LG2 and the immune signature were analyzed by exploring the TIMER2 and TISIDB databases. We also investigated correlations between CD274 and PDCD1LG2 and immunotherapeutic biomarkers, including mismatch repair (MMR), tumor mutation burden (TMB), microsatellite instability (MSI), and DNA methylation. Results: Expression levels of CD274 and PDCD1LG2 varied across multiple cancer types. CD274 and PDCD1LG2 not only impacted the prognosis of patients with cancer but were associated with clinical characteristics (lymph node metastasis, tumor stage, and sex) in kidney renal papillary cell carcinoma, thyroid carcinoma, and some other cancer types. Typically, CD274 and PDCD1LG2 could be strongly correlated with macrophages, dendritic cells, neutrophils, and CD8+ T-cells. Furthermore, CD274 and PDCD1LG2 expression were associated with various immunosuppressive biomarkers, such as CTLA4, TIGIT, and LAG3. In addition, CD274 and PDCD1LG2 were significantly associated with MMR, TMB, MSI, and DNA methylation. Finally, enrichment analysis confirmed that CD274 and PDCD1LG2 were associated with numerous biological pathways, such as: "Activation of Immune Reactions" and "Epithelial- Mesenchymal Transition," suggesting that CD274 and PDCD1LG2 play crucial roles in cancer immunity and tumor metastasis. Conclusion: CD274 and PDCD1LG2 play critical roles in cancer progression and immune response and could serve as effective biomarkers to predict the prognosis and immune signature of cancer. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian cancer (HGSOC) is a heterogeneous cancer characterized by high relapse rate. Approximately 80% of women are diagnosed with late-stage disease, and 15-25% of patients experience primary treatment resistance. Ovarian cancer brings tremendous suffering and is the most malignant type in all gynecologic malignancies. Metabolic reprogramming in tumor microenvironment (TME), especially fatty acid metabolism, has been identified to play a crucial role in cancer prognosis. Yet, the underlying mechanism of fatty acid metabolism on ovarian cancer progression is severely understudied. Recently, studies have demonstrated the role of fatty acid metabolism reprogramming in immune cells, but their roles on cancer cell metastasis and cancer immunotherapy response are poorly characterized. Here, we reported that the fatty acid-related genes are aberrantly varied between ovarian cancer and normal samples. Using samples in publicly databases and bio-informatic analyses with fatty acid-related genes, we disentangled that cancer cases can be classified into highand low-risk groups related with prognosis. Furthermore, the nomogram model was constructed to predict the overall survival. Additionally, we reported that different immune cells infiltration was presented between groups, and immunotherapy response differed in two groups. Results showed that our signature may have good prediction value on immunotherapy efficacy, especially for anti-PD-1 and anti-CTLA-4. Our study systematically marked the critical association between cancer immunity in TME and fatty acid metabolism, and bridged immune phenotype and metabolism programming in tumors, thereby constructed the metabolicrelated prognostic model and help to understand the underlying mechanism of immunotherapy response. [ABSTRACT FROM AUTHOR]

Considering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalian in vivo models remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, the in ovo model bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods for in and ex ovo monitoring of cellular and molecular dynamics already established in ovo are applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most fatal diseases in male patients with high bone metastatic potential. Bone metastasis severely shortens overall survival and brings skeletal-related events (SREs) which reduces the life quality of patients, and this situation is currently regarded as irreversible and incurable. The progression and metastasis of PCa are found to be closely associated with inflammatory cytokines and chemokines. As pivotal members of inflammatory cytokines, Interleukin-1 (IL-1) family plays a crucial role in this process. Elevated expression of IL-1 family was detected in PCa patients with bone metastasis, and accumulating evidences proved that IL-1 family could exert vital effects on the progression and bone metastasis of many cancers, while some members have dual effects. In this review, we discuss the role of IL- 1 family in the bone metastasis of PCa. Furthermore, we demonstrate that many members of IL-1 family could act as pivotal biomarkers to predict the clinical stage and prognosis of PCa patients. More importantly, we have elucidated the role of IL-1 family in the bone metastasis of PCa, which could provide potential targets for the treatment of PCa bone metastasis and probable directions for future research. [ABSTRACT FROM AUTHOR]

As a reversible and dynamic epigenetic modification, N6-methyladenosine (m6A) modification is ubiquitous in eukaryotic cells. m6A methylation is prevalent in almost all RNA metabolism processes that affect the fate of cells, including cancer development. As indicated by the available evidence, targeting m6A regulators may play a crucial role in tumor therapy and multidrug resistance. Currently, many questions remain uncovered. Here, we review recent studies on m6A modification in various aspects of tumor progression, tumor immunity, multidrug resistance, and therapeutic targets to provide new insight into the m6A methylation process. [ABSTRACT FROM AUTHOR]

Langerhans cells (LC) are a unique population of tissue-resident macrophages with dendritic cell (DC) functionality that form a network of cells across the epidermis of the skin. Their location at the skin barrier suggests an important role for LC as immune sentinels at the skin surface. The classification of LC as DC over the past few decades has driven the scientific community to extensively study how LC function as DC-like cells that prime T cell immunity. However, LC are a unique type of tissue-resident macrophages, and recent evidence also supports an immunoregulatory role of LC at steady state and during specific inflammatory conditions, highlighting the impact of cutaneous environment in shaping LC functionality. In this mini review, we discuss the recent literature on the immune tolerance function of LC in homeostasis and disease conditions, including malignant transformation and progression; as well as LC functional plasticity for adaption to microenvironmental cues and the potential connection between LC population heterogeneity and functional diversity. Future investigation into the molecular mechanisms that LC use to integrate different microenvironment cues and adapt immunological responses for controlling LC functional plasticity is needed for future breakthroughs in tumor immunology, vaccine development, and treatments for inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Lung cancer is currently the leading cause of cancer-related deaths worldwide. Significant improvements in lung cancer therapeutics have relied on a better understanding of lung cancer immunity and the development of novel immunotherapies, as best exemplified by the introduction of PD-1/PD-L1-based therapies. However, this improvement is limited to lung cancer patients who respond to anti-PD-1 immunotherapy. Further improvements in immunotherapy may benefit from a better understanding of innate immune response mechanisms in the lung. Toll-like receptors (TLRs) are a key component of the innate immune response and mediate the early recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling modulates the tumor microenvironment from “cold” to “hot” leading to immune sensitization of tumor cells to treatments and improved patient prognosis. In addition, TLR signaling activates the adaptive immune response to improve the response to cancer immunotherapy through the regulation of anti-tumor T cell activity. This review will highlight recent progress in our understanding of the role of TLRs in lung cancer immunity and immunotherapy.

Considering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalian in vivo models remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, the in ovo model bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods for in and ex ovo monitoring of cellular and molecular dynamics already established in ovo are applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology.

Acute lymphoblastic leukemia represents a malignant proliferation of lymphoid cells blocked at an early stage of cell differentiation. It is the most common cancer occurring in children. Despite favorable prognosis, the survival rate of patients with poor treatment response or relapse remains dismal. The interaction between leukemic cells and the tumor immune microenvironment is pivotal in mediating tumor progression. In this study we evaluated associations between Treg and Th17 lymphocytes and the clinical presentation of ALL pediatric patients to validate their value in monitoring treatment outcome. The peripheral blood and bone marrow aspirates from 35 pediatric patients with ALL and 48 healthy control subjects were selected for the experiment. We demonstrated the numbers of Th17 lymphocytes and Tregs were increased in the bone marrow of ALL patients at the moment of diagnosis compared to the healthy control group, with the latter significantly decreasing during the course of ALL treatment. Patients with lower Th17 were found to demonstrate higher risk of blasts prevalence in bone marrow at day 33. ALL patients with lower WBC demonstrated higher frequency of Tregs. In summary, we identified a significant role of Th17 and Treg lymphocytes in ALL of pediatric patients and their contribution to disease-related parameters.

Tumor microenvironment crosstalk, in particular interactions between cancer cells, T cells, and myeloid‐derived suppressor cells (MDSCs), mediates tumor initiation, progression, and response to treatment. However, current patient‐derived models such as tumor organoids and 2D cultures lack some essential niche cell types (e.g., MDSCs) and fail to model complex tumor‐immune interactions. Here, the authors present the novel acoustically assembled patient‐derived cell clusters (APCCs) that can preserve original tumor/immune cell compositions, model their interactions in 3D microenvironments, and test the treatment responses of primary tumors in a rapid, scalable, and user‐friendly manner. By incorporating a large array of 3D acoustic trappings within the extracellular matrix, hundreds of APCCs can be assembled within a petri dish within 2 min. Moreover, the APCCs can preserve sensitive and short‐lived (≈1 to 2‐day lifespan in vivo) tumor‐induced MDSCs and model their dynamic suppression of T cell tumor toxicity for up to 24 h. Finally, using the APCCs, the authors succesully model the combinational therapeutic effect of a multi‐kinase inhibitor targeting MDSCs (cabozantinib) and an anti‐PD‐1 immune checkpoint inhibitor (pembrolizumab). The novel APCCs may hold promising potential in predicting treatment response for personalized cancer adjuvant therapy as well as screening novel cancer immunotherapy and combinational therapy. [ABSTRACT FROM AUTHOR]