Exploring dendrimer-based drug delivery systems and their potential applications in cancer immunotherapy

Cyclin-dependent kinase inhibitor 2A (CDKN2A) encodes the cell senescence regulator protein p16. The expression of p16 raises in cell senescence and has a nuclear regulation in cell aging. Meanwhile, it's also reported to inhibit the aggression of several cancers. But its clinical application and role in cancer immunotherapy needs further investigation. We collected the transcriptional data of pan-cancer and normal human tissues from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. CBioPortal webtool was employed to mine the genomic alteration status of CDKN2A across cancers. Kaplan-Meier method and univariate Cox regression were performed for prognostic assessments across cancers, respectively. Gene Set Enrichment Analysis is the main method used to search the associated cancer hallmarks associated with CDKN2A. TIMER2.0 was used to analyze the immune cell infiltration relevance with CDKN2A in pan-cancer. The associations between CDKN2A and immunotherapy biomarkers or regulators were performed by spearman correlation analysis. We found CDKN2A is overexpressed in most cancers and exhibits prognosis predictive ability in various cancers. In addition, it is significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations and immunoregulators. The most interesting finding is that CDKN2A can significantly predict anti-PDL1 therapy response. Finally, specific inhibitors which correlated with CDKN2A expression in different cancer types were also screened by using Connectivity Map (CMap) tool. The results revealed that CDKN2A acts as a robust cancer prognostic and immunotherapy biomarker. Its function in the regulation of cancer cell senescence might shape the tumor microenvironment and contribute to its predictive ability of immunotherapy.

Cancer immunotherapy approaches have progressed significantly during the last decade due to the significant improvement of our understanding of immunologic evasion of malignant cells. Depending on the type, stage, and grade of cancer, distinct immunotherapy approaches are being designed and recommended; each is different in efficacy and adverse effects. Malignant cells can adopt multiple strategies to alter the normal functioning of the immune system in recognizing and eliminating them. These strategies include secreting different immunosuppressive factors, polarizing tumor microenvironment cells to immunosuppressive ones, and interfering with the normal function of the antigen processing machinery (APM). In this context, careful evaluation of immune surveillance has led to a better understanding of the roles of cytokines, including IL-2, IL-12, IL-15, interferon-α (IFN-α), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) in cancer formation and their potential application in cancer immunotherapy. Additionally, monoclonal antibodies (mAbs), adoptive cell therapy approaches, immune checkpoint blockade, and cancer vaccines also play significant roles in cancer immunotherapy. Moreover, the development of clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/CAS9) as an outstanding genome editing tool resolved many obstacles in cancer immunotherapy. In this regard, this review aimed to investigate the impacts of different immunotherapy approaches and their potential roles in the current and future roads of cancer treatment. Whatever the underlying solution for treating highly malignant cancers is, it seems that solving the question is nowhere near an achievement unless the precise cooperation of basic science knowledge with our translational experience.

Advances in Immunogenic Cell Death for Cancer Immunotherapy

Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells and B cells. Recent studies have revealed that interleukin-15 also plays a critical role in cancer immunotherapy. Interleukin-15 agonist molecules have shown that interleukin-15 agonists are effective in inhibiting tumor growth and preventing metastasis, and some are undergoing clinical trials. In this review, we will summarize the recent progress in interleukin-15 research over the past 5 years, highlighting its potential applications in cancer immunotherapy and the progress of interleukin-15 agonist development.

The adaptive immune checkpoints such as PD-1(programmed death-1)/PD-L1 (programmed death-ligand 1) play an important role in cancer immunotherapy, whereas increasing evidence suggests that cancer cell evades immune surveillance by innate immune checkpoints such as SIRPα (signal-regulatory protein α)/CD47 (cluster of differentiation 47). In multiple types of cancer cells and solid tumor tissues, highly expressed CD47 protein level has been observed, which is triggered by some transcription factors including NFκB, Myc, and HIF. As a transmembrane protein, the binding of CD47 to SIRPα ligand on phagocytes results in phagocytosis resistance and cancer cell immune escape. In contrast, CD47-SIRPα interaction blockade enhances cancer cell clearance by phagocytes such as macrophages and dendritic cells (DCs) to activate an innate immune response, whereas this process could promote antigen cross-presentation by antigen present cells (APCs) leading to T cell priming, consequently, activates an adaptive antitumor immune response. In this review, we discussed the current SIRPα-CD47 axis-mediated cancer cell immune escape and immunotherapy, which could provide an effective antitumor strategy by the innate and adaptive immune response.

Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications

Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy.

Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up-regulated expression of co-inhibitory receptors, including programmed death-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co-inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti-tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes. HIGHLIGHTS: This review discusses five major co-inhibitory receptors (PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT) and their related mechanisms of T cell exhaustion in the tumour environment. We also discuss the clinical application of checkpoint inhibitors (ICIs) in cancer immunotherapy. The potential of bispecific antibodies (BsAbs) in cancer immunotherapy is highlighted.

Immune cells, such as cytotoxic T lymphocytes, natural killer cells, B cells, and dendritic cells, have a central role in cancer immunotherapy. Conventional studies of cancer immunotherapy have focused mainly on the search for an efficient means to prime/activate tumor-associated antigen-specific immunity. A systematic understanding of the molecular basis of the trafficking and biodistribution of immune cells, however, is important for the development of more efficacious cancer immunotherapies. It is well established that the basis and premise of immunotherapy is the accumulation of effective immune cells in tumor tissues. Therefore, it is crucial to control the distribution of immune cells to optimize cancer immunotherapy. Recent characterization of various chemokines and chemokine receptors in the immune system has increased our knowledge of the regulatory mechanisms of the immune response and tolerance based on immune cell localization. Here, we review the immune cell recruitment and cell-based systems that can potentially control the systemic pharmacokinetics of immune cells and, in particular, focus on cell migrating molecules, i.e., chemokines, and their receptors, and their use in cancer immunotherapy.

Cancer immunotherapy has shown significant potential in treating several malignancies by stimulating the host immune system to recognize and attack cancer cells. Immunogenic cell death (ICD) can amplify the antitumor immune responses and reverse the immunosuppressive tumor microenvironment, thus increasing the sensitivity of cancer immunotherapy. In recent years, noncoding RNAs (ncRNAs) have emerged as key regulatory factors in ICD and oncologic immunity. Accordingly, ICD-related ncRNAs hold promise as novel therapeutic targets for optimizing the efficacy of cancer immunotherapy. However, the immunomodulatory properties of ICD-related ncRNAs have not yet been comprehensively summarized. Hence, we summarize the current knowledge on ncRNAs involved in ICD and their potential roles in cancer immunotherapy in this review. It deepens our understanding of ncRNAs associated with ICD and provides a new strategy to enhance cancer immunotherapy by specifically targeting the ICD-related ncRNAs.

Simple SummaryIn recent years, immunotherapy has shown great advancement, becoming a powerful tool to combat cancer. In this context, the use of biologically derived vesicles has also acquired importance for cancer immunotherapy. Extracellular vesicles are thus proposed to transport molecules able to trigger an immune response and thus fight cancer cells. As a particular immunotherapeutic approach, a new technique also consists in the exploitation of extracellular vesicles as new cancer vaccines. The present review provides basic notions on cancer immunotherapy and describes several clinical trials in which therapeutic anticancer vaccines are tested. In particular, the potential of extracellular vesicles-based therapeutic vaccines in the treatment of cancer patients is highlighted, even with advanced stage-cancer. A focus on the clinical studies, already completed or still in progress, is offered and a systematic collection and reorganization of the present literature on this topic is proposed to the reader.Extracellular vesicles (EVs) are natural particles formed by the lipid bilayer and released from almost all cell types to the extracellular environment both under physiological conditions and in presence of a disease. EVs are involved in many biological processes including intercellular communication, acting as natural carriers in the transfer of various biomolecules such as DNA, various RNA types, proteins and different phospholipids. Thanks to their transfer and targeting abilities, they can be employed in drug and gene delivery and have been proposed for the treatment of different diseases, including cancer. Recently, the use of EVs as biological carriers has also been extended to cancer immunotherapy. This new technique of cancer treatment involves the use of EVs to transport molecules capable of triggering an immune response to damage cancer cells. Several studies have analyzed the possibility of using EVs in new cancer vaccines, which represent a particular form of immunotherapy. In the literature there are only few publications that systematically group and collectively discuss these studies. Therefore, the purpose of this review is to illustrate and give a partial reorganization to what has been produced in the literature so far. We provide basic notions on cancer immunotherapy and describe some clinical trials in which therapeutic cancer vaccines are tested. We thus focus attention on the potential of EV-based therapeutic vaccines in the treatment of cancer patients, overviewing the clinically relevant trials, completed or still in progress, which open up new perspectives in the fight against cancer.

At the clinical level the role of immunotherapy in cancer is currently at a pivotal point. Therapies such as checkpoint inhibitors are being approved at many levels in cancers such as non-small cell lung cancer (NSCLC). Mesothelioma is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Various clinical trials for checkpoint inhibitors have been conducted in this rare disease, and suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Most recently approved as a salvage therapy in mesothelioma was granted in Japan, regulatory approval for their use in the clinic elsewhere lags. In this article we review the current pertinent clinical trials of immunotherapies in malignant mesothelioma, discuss the current issues that may affect the clinical outcomes of such therapies and further evaluate potential candidate new avenues that may become future targets for immunotherapy in this cancer.

Introduction: Immunotherapy represents an emerging modality of treatment utilized in patients with prostate cancer, among various other malignancies.Areas covered: Sipuleucel-T is an autologous active cellular immunotherapy that has demonstrated improved survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The IMPACT trial led to the FDA approval of sipuleucel-T as first-line treatment for men with asymptomatic or minimally symptomatic mCRPC. Additional immunotherapies in cancer have shown promising results in clinical studies. These include ProstVac, which is a poxvirus vaccine targeting prostate-specific antigen, and cell cycle checkpoint inhibitors of cytotoxic T lymphocyte antigen-4 and programmed death-1 (PD-1) and its ligand (PD-L1). The combination of sipuleucel-T with both androgen deprivation therapy and androgen signaling agents has demonstrated robust and augmented immune responses. The responses to immunotherapy are often seen via different parameters compared with other therapies, including increased T-cell activation and antibody response.Expert opinion: The role of immunotherapy in cancer continues to grow and encompass agents with different mechanisms, and ongoing efforts to identify appropriate timing of therapy and patients for use is integral to the management of prostate cancer.

Nano-, micro-, and macroscale drug delivery systems for cancer immunotherapy

Significance: Microbial neurotransmitters, as potential targets for cancer therapy, are expected to provide a new perspective on the interaction between the gut microbiome and cancer immunotherapy. Recent Advances: Mounting data reveal that most neurotransmitters can be derived from gut microbiota. Furthermore, modulation of neurotransmitter signaling can limit tumor growth and enhance antitumor immunity. Critical Issues: Here, we first present the relationships between microbial neurotransmitters and cancer cells mediated by immune cells. Then, we discuss the microbial neurotransmitters recently associated with cancer immunotherapy. Notably, the review emphasizes that neurotransmitter signaling plays a substantial role in cancer immunotherapy as an emerging cancer treatment target by regulating targeted receptors and interfering with the tumor microenvironment. Future Directions: Future studies are required to uncover the antitumor mechanisms of neurotransmitter signaling to develop novel treatment strategies to overcome cancer immunotherapy resistance. Antioxid. Redox Signal. 38, 298-315.