Immune checkpoint inhibitor (ICI) have demonstrated efficacy in treating various cancers by modulating the immune system, but this can lead to immune-related adverse events (irAEs), including myocarditis. ICI-associated myocarditis is a rare but highly lethal irAE with a short mean time to onset, and difficult to diagnose early due to nonspecific symptoms and lack of biomarkers. This review highlights the need for improved recognition and management of ICI-associated myocarditis, summarizing recent advances in immunology, pathology, and biomarker research. We discuss the epidemiology, clinical features, immunological mechanisms, and roles of biomarkers in diagnosis and risk stratification. Traditional biomarkers like cTnI and hs-cTnT are sensitive but lack specificity, while emerging biomarkers like miR-155 show tissue specificity. Inflammatory markers such as NLR and CRP aid prognosis but have limited diagnostic value.

Regulatory T cell (Treg cell) therapy has been transformed through the use of chimeric antigen receptors (CARs). We previously found that human Treg cells minimally produce IL-10 and have a limited capacity to control innate immunity compared to type 1 regulatory T cells (Tr1 cells). To create "hybrid" CAR Treg cells with Tr1 cell-like properties, we examined whether the PDCD1 locus could be exploited to endow Treg cells with CAR-regulated IL-10 expression. CRISPR-mediated PD1 deletion increased CAR Treg cell activation, and knock-in of IL10 under control of the PD1 promoter resulted in CAR-induced IL-10 secretion. IL10 knock-in improved CAR Treg cell function, as determined by increased suppression of dendritic cells and alloantigen- and islet autoantigen-specific T cells. In vivo, IL10 knock-in CAR Treg cells were stable, safe, and suppressed dendritic cells and xenogeneic graft-versus-host disease. CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance a suppressive mechanism is a previously unexplored approach to improve CAR Treg cell potency.

Regulatory T (Treg) cells are vital for immune suppression. The role of the coreceptor programmed cell death 1 receptor (PD-1) in Treg cell function is controversial. Here, we demonstrate that PD-1 deficiency enhances the function of Treg cells through expression of a compensatory network of coinhibitory receptors. CD30 has a central role within this network, driving the Treg cell suppressive function within the tumor microenvironment. Mechanistically, PD-1 deficiency enhances STAT5 signaling in Treg cells, which induces CD30 expression. These data indicate a role for PD-1 as a checkpoint that negatively controls CD30 expression in Treg cells to limit their suppressive function. Understanding the functional changes that PD-1 has on Treg cells might enable combination therapies with better treatment outcomes in cancer.

The incidence rate of COVID-19-associated pulmonary aspergillosis (CAPA) is rising. However, the pathogenesis of CAPA remains unclear. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection disrupts pathways related to type I interferon and Toll-like receptors, key components in innate immunity, thereby elevating the incidence of CAPA. Additionally, SARS-CoV-2 infection results in T and B cell functional deficiencies or exhaustion within adaptive immunity, weakening the defense against invasive Aspergillus. Furthermore, SARS-CoV-2 infection enhances the replication of cytomegalovirus and alters the gut microbiota, factors that may aid in diagnosing CAPA. Immunosuppressive therapy in COVID-19 patients is also believed to heighten the risk of invasive aspergillosis. Therefore, this review, examines the immune response to SARS-CoV-2 infection combined with invasive aspergillosis, and explores the pathogenesis and susceptibility factors of CAPA. We propose that variations in an individual's immune response significantly determine susceptibility to CAPA. The aim of this paper is to deepen clinical understanding of CAPA's pathogenesis, thereby aiding in mitigating susceptibility risk and advancing novel treatment approaches.

Persisting programmed cell death-1 (PD-1) signaling impairs T cell effector function, which is highly associated with T cell exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes PD-1 protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates the USP24 expression, which leads to PD-1 stabilization. Furthermore, USP24 deficiency reduces PD-1 levels in CD8+ T cells and attenuates EgfrL858R-driven lung tumorigenesis in Usp24C1695A catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic T cell activity, restrains lung tumor growth, and achieves superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, patients with lung cancer exhibiting high USP24 expression in tumor-infiltrating CD8+ T cells display exhausted features and show unfavorable responses to immunotherapy. Our findings dissect the mechanism for regulating enhanced PD-1 stability in tumor-infiltrating CD8+ T cells and reveal USP24 as a potential target of antitumor immunotherapy.

Presented is a 76-year-old man with metastatic melanoma that was successfully treated with pembrolizumab, an immune checkpoint inhibitor (ICI). He underwent 20 months of ICI treatment without dose limiting side effects. Nearly 18 months after ICI discontinuation, the patient developed intermittent epigastric pain and diarrhea. Owing to mild symptoms, he was not immediately evaluated. Three years after ICI cessation, he was diagnosed with stricturing, jejunal Crohn's disease. He was treated with vedolizumab and displayed clinical and radiographic response to treatment. This case serves as an example of potential gastrointestinal-related, long-term autoimmune implications of ICI therapy, even in patients without acute side effects.

Regulatory T cells (Tregs) are important in maintaining tolerance and are key players in immunity. In aging, increased Treg function along with low-grade inflammation has been reported. This dichotomy of enhanced Treg function along with inflammation highlights the importance of understanding Treg biology and communication patterns in the very old. In this proof-of-concept study, we demonstrate that aged Tregs (85 years) do not significantly communicate with CD4+ and CD8+ T effectors when compared with healthy < 66-year-olds. Of note was the enhanced communication of aged Tregs with CD3+CD8+CD56+CD161- NK-like T-cell populations, which are important in antitumor and chronic viral diseases in older individuals. We found that in turn this population of killer-like T cells showed diminished cytotoxic characteristics, and killer receptor expression. Taken together, our proof-of-concept study delineates the biology of Tregs and identifies previously undefined communication patterns in the very old.

The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.

Malignant melanoma is characterized by high immunogenicity, genetic heterogeneity, and diverse pathological manifestations, affecting both skin and mucosa over the body. Pembrolizumab and nivolumab, both anti-PD-1 monoclonal antibodies, were approved by the US FDA for unresectable or metastatic melanoma in 2011 and 2014, respectively, with enduring and transformative outcomes. Despite marked clinical achievements, only a subset of patients manifested a complete response. Approximately 55% of melanoma patients exhibited primary resistance to PD-1 antibodies, with nearly 25% developing secondary resistance within 2 years of treatment. Thus, there is a critical need to comprehensively elucidate the mechanisms underlying the efficacy and resistance to PD-1 blockade. This review discusses the fundamental mechanisms of PD-1 blockade, encompassing insights from T cells and B cells, and presents resistance to anti-PD-1 with a particular focus on tumoral-intrinsic mechanisms in melanoma.

Anti-programmed cell death protein 1 (anti-PD-1) antibodies have achieved revolutionary success in cancer therapy. However, the impact of anti-PD-1 therapy on host humoral immunity in humans during cancer immunotherapy requires further investigation.

We evaluated immunoglobulin titers by ELISA and screened the immune landscape of immune cells from 25 healthy donors and 50 cases including 25 new-onset hepatocellular carcinoma (HCC) patients prior to systemic treatment and 25 HCC patients undergoing anti-PD-1 therapy by multicolor flow cytometry. Flow or beads sorted cells were cultured ex vivo for proliferation and functional analysis.

Anti-PD-1 therapy significantly increased the levels of IgG and IgA in the periphery of HCC patients. Anti-PD-1 treatment led to an increase in plasmablasts and a notable rise in circulating T follicular regulatory (cTfr) cells, while changes in circulating B cells, T follicular helper cells, or regulatory T cells were not significant. Anti-PD-1 therapy also influenced the proliferation and function of cTfr cells, promoting the differentiation of CD38+ cTfr cells. We observed that the CD38+ Tfr cell subset in the peripheral blood can promote plasmablast differentiation, associated with altered antibody production.

Together, these data demonstrate the immunomodulatory role of PD-1 in restricting the differentiation and function of human cTfr cells and in regulating humoral immunity.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that often leads to end-stage renal disease, with disease progression deeply influenced by the renal microenvironment. This study aims to unravel the critical cellular types and their intricate interactions within the ADPKD microenvironment.

Leveraging single-cell transcriptome data from seven ADPKD and three healthy human kidney samples, we systematically dissected the cellular landscape of the ADPKD microenvironment. Our approach included CellChat for cell-cell communication analysis, VISION for pathway enrichment analysis, pySCENIC for regulon activity calculation, and Monocle V3 for pseudotime trajectory construction.

We identified nine major cell lineages, with a notable increase of mononuclear phagocytes (MNPs), T cells, and fibroblasts in the ADPKD microenvironment. These cells collectively orchestrated a distinctive microenvironment, marked by complex intercellular networks. Notably, a specific subset of macrophages exhibited an "M2-like" phenotype, which was driven by IL-10 signaling from M1-like macrophages and contributed to cyst cell proliferation. Immunosuppression was predominantly mediated by CD4+ T cells, activated by macrophages through immune checkpoint pathways, such as PDL1 signaling. The fibrotic expansion was a cumulative effect of fibroblast activation and proliferation, modulated by macrophages and cyst-lining epithelial cells.

This comprehensive investigation provides valuable insights into the diverse landscapes of the ADPKD microenvironment at single-cell resolution, emphasizing MNPs, T cells, and fibroblasts. The study unveils complex interactions among these cell types, shedding light on an understanding of the immunological aspect of ADPKD and proposing potential therapeutic targets.

Regulatory T cells (Tregs) are immune regulatory T cells that are vital for controlling inflammation. The role of Tregs in inflammatory diseases namely psoriatic arthritis (PsA) is still poorly understood. The underlying reason being a lack of robust unbiased analysis to test the immune regulatory phenotype of human Tregs. Here, we propose that checkpoint receptors can identify functional Tregs in PsA. Using unbiased BD Rhapsody single-cell analysis, we have analyzed the expression pattern of checkpoint receptors in Tregs and found that PsA Tregs are enriched in the expression of CTLA4, TIGIT, PD-1, and GITR while TIM3 was downregulated. Furthermore, PD-1+ Tregs in PsA had an increased type 1 phenotype and expressed the protease asparaginyl endopeptidase. By harnessing the PD-1 signaling pathway and inhibiting asparaginyl endopeptidase, PsA Treg function was significantly enhanced in in vitro suppressor assays. Next, we interrogated the cell interaction pathways of Tregs in PsA and found a diminished crosstalk with circulating osteoclast precursors through the CD244-CD48 coreceptor pathways. Therapeutically, PsA Treg function could be enhanced by modulating PD-1 and osteoclast interactions. Our study suggests that unconventional immune cell crosstalk with Tregs is severely diminished in PsA.

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15Ink4b, p21Cip1, p27Kip1, and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy.

Neurological disorders such as Alzheimer's disease (AD), and Parkinson's disease (PD) have no disease-modifying treatments, resulting in a global dementia crisis that affects more than 50 million people. Amyloid-beta (Aβ), tau, and alpha-synuclein (α-Syn) are three crucial proteins that are involved in the pathogenesis of these age-related neurodegenerative diseases. Only a few approved AD medications have been used in the clinic up to this point, and their results are only partial symptomatic alleviation for AD patients and cannot stop the progression of AD. Immunotherapies have attracted considerable interest as they target certain protein strains and conformations as well as promote clearance. Immunotherapies also have the potential to be neuroprotective: as they limit synaptic damage and spread of neuroinflammation by neutralizing extracellular protein aggregates. Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aβ monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aβ) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aβ and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aβ (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate the therapeutic possibilities and adverse effects of these anti-Aβ and anti-αSyn MAbs on AD and PD.

Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.

The interplay between regulatory T cells (Tregs) and neighboring cells, which is pivotal for anti-tumor immunity and closely linked to patient prognosis, remains to be fully elucidated.

Tissue microarrays of 261 operable NSCLC patients were stained by multiplex immunofluorescence (mIF) assay, and the interaction between Tregs and neighboring cells in the tumor microenvironment (TME) was evaluated. Employing various machine learning algorithms, we developed a spatial immune signature to predict the prognosis of NSCLC patients. Additionally, we explored the interplay between programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interactions and their relationship with Tregs.

Survival analysis indicated that the interplay between Tregs and neighboring cells in the invasive margin (IM) and tumor center was associated with recurrence in NSCLC patients. We integrated the intersection of the three algorithms to identify four crucial spatial immune features [P(CD8+Treg to CK) in IM, P(CD8+Treg to CD4) in IM, N(CD4+Treg to CK) in IM, N(CD4+Tcon to CK) in IM] and employed these characteristics to establish SIS, an independent prognosticator of recurrence in NSCLC patients [HR = 2.34, 95% CI (1.53, 3.58), P < 0.001]. Furthermore, analysis of cell interactions demonstrated that a higher number of Tregs contributed to higher PD-L1+ cells surrounded by PD-1+ cells (P < 0.001) with shorter distances (P = 0.004).

We dissected the cell interplay network within the TME, uncovering the spatial architecture and intricate interactions between Tregs and neighboring cells, along with their impact on the prognosis of NSCLC patients.

Background Studies have shown that aberrant reactions of the immune system play an important role in the pathogenesis of preeclampsia. The immune checkpoint molecules programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) system and the T-regulatory cells (Tregs) system are decisive in the regulation of immune responses and can be the target molecules in preeclampsia. In this study, an attempt has been made to evaluate the soluble PD-L1 (sPD-L1) in the serum of preeclampsia cases and correlate it with Tregs and inflammatory markers to have an insight into the link between these immunomodulatory molecules in the pathogenesis of preeclampsia. Materials and methods Ten normal fertile women, 20 trimester-matched normal pregnancy cases, and 20 preeclampsia cases were enrolled in the study. Serum sPD-L1, transforming growth factor beta 1 (TGF-β1), and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). High-sensitive C-reactive protein (hsCRP) was estimated using a clinical biochemistry autoanalyzer. Tregs were evaluated using flow cytometry. Results and discussion The immune checkpoint molecule PD-L1 inversely correlated with Tregs in preeclampsia cases. Associated inflammation was seen by raised IL-6 and hsCRP. The breakdown of immunological tolerance is mainly caused by the dysregulating the Tregs/Th17 balance, which leads to conditions of autoimmunity and chronic inflammatory disorders. PD-L1 can be the link between this immunological misbalance. Conclusion Our study, showing an increase in sPD-L1 and TGF and a decrease in Tregs with an increase in inflammatory markers like IL-6 and hsCRP levels in preeclampsia, has potential implications for early diagnosis and management of the condition. PD-L1 and Tregs can be target molecules for early management of preeclampsia.

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4+ T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE.

Surface expression of programmed death-ligand 1 (PD-L1) is mainly observed on antigen presenting cells (APC) such as monocytes or dendritic cells (DCs). Our results showing a high expression of PD-L1 on human naïve CD4+ effector T-cells (TEFFs) and CD4+ regulatory T cells (TREGs) after activation with human DCs, allow us to propose a new role for PD-L1 and its ligands and their potential impact on new signaling pathways. Indeed, expression of PD-L1 on activated CD4+T cells could allow cis interaction with its ligands such as PD-1 and CD80, thus disrupting interactions with other signaling receptors, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or CD28, which interact with CD80. The ability to compete with hypothetical configuration modifications that may cause a change in affinity/avidity for the trans and cis interactions between these proteins expressed on T cells and/or DCs is discussed. As the study of cancer is strongly influenced by the role of the PD-L1/PD-1 pathway and CD4+T cells, new interactions, cis and/or trans, between TEFFs, TREGs and tumor cells are also proposed. The presence of PD-L1 on activated CD4+ T cells could influence the quality of the cytotoxic T lymphocyte response during priming to provide other help signals.

The mechanisms that negatively regulate inflammation upon a pathogenic stimulus are crucial for the maintenance of tissue integrity and organ function. T regulatory cells are one of the main drivers in controlling inflammation. The ability of T regulatory cells to adapt to different inflammatory cues and suppress inflammation is one of the relevant features of T regulatory cells. During this process, T regulatory cells express different transcription factors associated with their counterparts, Th helper cells, including Tbx21, GATA-3, Bcl6, and Rorc. The acquisition of this transcription factor helps the T regulatory cells to suppress and migrate to the different inflamed tissues. Additionally, the T regulatory cells have different mechanisms that preserve stability while acquiring a particular T regulatory cell subtype. This review focuses on describing T regulatory cell subtypes and the mechanisms that maintain their identity in health and diseases.

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.

Radiotherapy (RT) remodels the tumor immune microenvironment (TIME) and modulates the immune response to indirectly destroy tumor cells, in addition to directly killing tumor cells. RT combined with immunotherapy may significantly enhance the efficacy of RT in colorectal cancer by modulating the microenvironment. However, the molecular mechanisms by which RT acts as an immunomodulator to modulate the immune microenvironment remain unclear. Further, the optimal modalities of RT combined with immunotherapy for the treatment of colorectal cancer, such as the time point of combining RT and immunization, the fractionation pattern and dosage of radiotherapy, and other methods to improve the efficacy, are also being explored parallelly. To address these aspects, in this review, we summarized the mechanisms by which RT modulates TIME and concluded the progress of RT combined with immunization in preclinical and clinical trials. Finally, we discussed heavy ion radiation therapy and the efficacy of prediction markers and other immune combination therapies. Overall, combining RT with immunotherapy to enhance antitumor effects will have a significant clinical implication and will help to facilitate individualized treatment modalities.

Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients.

The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients.

PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy.

Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.

Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune-related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI-induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non-ICI drug-induced TIN. Age and C-reactive protein levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI-induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.

Immunotherapy plays a vital role in cancer postoperative treatment. Strategies to increase the variety of immune cells and their sustainable supply are essential to improve the therapeutic effect of immune cell-based immunotherapy. Here, inspired by tertiary lymphoid structures (TLSs), we present a microfluidic-assisted microporous annealed particle (MAP) scaffold for the persistent recruitment of diverse immune cells for cancer postoperative therapy. Based on the thermochemical responsivity of gelatin methacryloyl (GelMA), the MAP scaffold was fabricated by physical cross-linking and sequential photo-cross-linking of GelMA droplets, which were prepared by microfluidic electrospraying. Due to the encapsulation of liquid nitrogen-inactivated tumor cells and immunostimulant, the generated MAP scaffold could recruit a large number of immune cells, involving T cells, macrophages, dendritic cells, B cells, and natural killer cells, thereby forming the biomimetic TLSs in vivo. In addition, by combination of immune checkpoint inhibitors, a synergistic anticancer immune response was provoked to inhibit tumor recurrence and metastasis. These properties make the proposed MAP scaffold-based artificial TLSs of great value for efficient cancer postoperative therapy.

An increase in the incidence of melanoma has been observed in recent decades, which poses a significant challenge due to its poor prognosis in the advanced and metastatic stages. Previously, chemotherapy and high doses of interleukin-2 were available treatments for melanoma; however, they offered limited survival benefits and were associated with severe toxicities. The treatment of metastatic melanoma has been transformed by new developments in immunotherapy. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PDL-1, have emerged as promising therapeutic options. Commonly used ICIs, such as ipilimumab, nivolumab and pembrolizumab, have been found to be associated with an improved median overall survival, recurrence-free survival and response rates compared to traditional chemotherapies. Combination therapies involving different types of ICIs, such as anti-PD1 with anti-CTLA-4, have further enhanced the overall survival and response rates by targeting various phases of T-cell activation. Additionally, the development of novel biomarkers has facilitated the assessment of responses to ICI therapy, with tissue and serum-based prognostic and predictive biomarkers now available. The increased response observed with ICIs also provides potential for immune-related adverse effects on various organ systems. Further research is required to evaluate the efficacy and safety of various combinations of ICIs, while ongoing clinical trials explore the potential of newer ICIs. Concerns regarding the development of resistance to ICIs also warrant attention. The present review summarizes and discusses the advent of ICIs with a marked significant breakthrough in the treatment of metastatic melanoma, providing improved outcomes compared to traditional therapies.

We investigated expressions of PD-L1, LAG-3, TIM-3, and OX40L as immune checkpoint proteins, and MSI (repetitive short-DNA-sequences due to defective DNA-repair system) status were analyzed with immunohistochemistry from tissue blocks. Of 83 patients, PD-L1 expression was observed in 18.1% (n = 15) of the patients. None of the patients exhibited LAG-3 expression. TIM-3 expression was 4.9% (n = 4), OX40L was 22.9% (n = 19), and 8.4% (n = 7) of the patients had MSI tumor. A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients' quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates.

Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Pituitary neuroendocrine tumors (PitNETs) are the most common pituitary tumors and the second most common brain tumors. Although the vast majority (>90%) are benign, a small percentage (<2%) are aggressive. These aggressive PitNETs (AgPitNETs) are defined by the presence of radiological invasion, a high rate of cell proliferation, resistance to conventional treatments, and/or a high propensity for recurrence. Lastly, there are the rare pituitary carcinomas, also known as metastatic PitNETs (MetPitNETs), which account for only 0.2% of cases and are defined by the presence of craniospinal or distant metastases. At present, there are no definitive factors that allow us to predict with certainty the aggressive behavior of PitNETs, making the therapeutic management of AgPitNETs a real challenge. Surgery is considered the first-line treatment for AgPitNETs and MetPitNETs. Radiation therapy can be effective in controlling tumor growth and regulating hormone hypersecretion. Currently, there are no approved non-endocrine medical therapies for the management of AgPitNETs/MetPitNETs, mainly due to the lack of randomized controlled clinical trials. As a result, many of the medical therapies used are off-label drugs, and several are under investigation. Temozolomide (TMZ) is now recognized as the primary medical treatment following the failure of standard therapy (medical treatment, surgery, and radiotherapy) in AgPitNETs/MetPitNETs due to its ability to improve overall and progression-free survival rates in responding patients over 5 years. Other therapeutic options include pituitary-targeted therapies (dopamine agonists and somatostatin analogs), hormonal antisecretory drugs, non-hormonal targeted therapies, radionuclide treatments, and immunotherapy. However, the number of patients who have undergone these treatments is limited, and the results obtained to date have been inconsistent. As a result, it is imperative to expand the cohort of patients undergoing treatment to better determine the therapeutic efficacy and safety of these drugs for individuals with AgPitNETs/MetPitNETs.

Glioblastoma (GB) is an aggressive and deadly brain tumor with a poor prognosis despite the current standard of care, including surgery, radiation, and chemotherapy.

In recent years, there has been increasing interest in the potential of immunotherapies, seen to be effective in treating other cancers, in the treatment of GB. This comprehensive review presents an in-depth analysis of the remarkable progress of immunotherapy in GB treatment, focusing on human clinical studies. It also analyzes the current findings, challenges, and limitations that underscore the transformative potential of immunotherapy in managing GB. Of particular significance, it delves into the intriguing interaction of the human microbiome with immunotherapy as a novel avenue for enhancing treatment outcomes of GB.

This study sheds light on the complex GB therapy landscape and the cutting-edge strategies that show promise for enhancing patient prognosis.

Gliomas are one of the most common primary malignant tumours of the central nervous system (CNS), of which glioblastomas (GBMs) are the most common and destructive type. The glioma tumour microenvironment (TME) has unique characteristics, such as hypoxia, the blood-brain barrier (BBB), reactive oxygen species (ROS) and tumour neovascularization. Therefore, the traditional treatment effect is limited. As cellular oxidative metabolites, ROS not only promote the occurrence and development of gliomas but also affect immune cells in the immune microenvironment. In contrast, either too high or too low ROS levels are detrimental to the survival of glioma cells, which indicates the threshold of ROS. Therefore, an in-depth understanding of the mechanisms of ROS production and scavenging, the threshold of ROS, and the role of ROS in the glioma TME can provide new methods and strategies for glioma treatment. Current methods to increase ROS include photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), etc., and methods to eliminate ROS include the ingestion of antioxidants. Increasing/scavenging ROS is potentially applicable treatment, and further studies will help to provide more effective strategies for glioma treatment.

Keratoacanthoma (KA) is a common keratinocyte neoplasm that is regularly classified as a type of cutaneous squamous cell carcinoma (cSCC) despite demonstrating benign behavior. Differentiating KA from well-differentiated cSCC is difficult in many cases due to the substantial overlap of clinical and histological features. Currently, no reliable discriminating markers have been defined, and consequently, KAs are often treated similarly to cSCC, creating unnecessary surgical morbidity and healthcare costs. In this study, we used RNA sequencing to identify key differences in transcriptomes between KA and cSCC, which suggested divergent keratinocyte populations between each tumor. Imaging mass cytometry was then used to identify single-cell tissue characteristics, including cellular phenotype, frequency, topography, functional status, and interactions between KA and well-differentiated cSCC. We found that cSCC had significantly increased proportions of Ki67+ keratinocytes among tumor keratinocytes, which were dispersed significantly throughout non-basal keratinocyte communities. In cSCC, regulatory T-cells were more prevalent and held greater suppressive capacity. Furthermore, cSCC regulatory T-cells, tumor-associated macrophages, and fibroblasts had significant associations with Ki67+ keratinocytes as opposed to avoidances with KA, indicating a more immunosuppressive environment. Our data suggest that multicellular spatial features can serve as a foundation to enhance the histological discrimination of ambiguous KA and cSCC lesions.

To investigate the influence of strain differences in immune response on the pathogenesis of oral candidiasis in Dark Agouti (DA) and Albino Oxford (AO) inbred strains of rats.

Seventy male 8-weeks old DA and AO rats were inoculated with Candida albicans to induce three different experimental models of oral candidiasis, one immunocompetent and two immunocompromised models. The animals were sacrificed after 16 days from the beginning of the experiment followed by collecting the samples of the tongue dorsum and blood for histopathological (PAS and H&E staining), immunohistochemical, qRT-PCR, and oxidative stress analyses.

Histopathological and immunohistochemical analyses revealed lower levels of epithelial colonization, epithelial damage, and inflammatory infiltration in DA compared to AO strain of rats. DA rats had fewer CD45, CD68, and CD3 positive cells but more HIS 48 positive cells than AO rats. The expressions of IL-1β, TNFα, IFN-γ, IL-10 and TGF-β1 were consistently higher in DA strain across all experimental models. However, the expressions of IL-4 and IL-17 differed inconsistently between DA and AO strain in various experimental models. Strain differences were observed in levels of prooxidative hydrogen peroxide and lipid peroxidation, with higher levels presented in AO rats compared to DA rats, while antioxidative parameters presented little yet inconsistent difference between strains.

DA strain of rats consistently presented lower susceptibility to oral infection with C. albicans compared to AO strain with robust Th1/Th17 immune response indicating the importance of the genetic background on the development of oral candidiasis.

Gastric cancer (GC) is a highly aggressive malignancy that remains a significant contributor to cancer-related mortality worldwide, despite a decline in incidence in recent years. Early-stage GC poses a diagnostic challenge due to its asymptomatic nature, leading to poor prognoses for most patients. Conventional treatment approaches, including chemotherapy and surgery, have shown limited efficacy in improving outcomes for GC patients. The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, yielding durable responses across various malignancies. However, the clinical benefits of ICIs in GC have been modest, underscoring the need for a comprehensive understanding of immune cell functions within the GC tumor microenvironment (TME). Regulatory T cells (Tregs), a subset of T lymphocytes, play a pivotal role in GC development and progression and serve as prognostic biomarkers for GC patients. This review aims to elucidate the multifaceted roles of Tregs in the pathogenesis, progression, and prognosis of gastric cancer, and establish their actual and future potential as therapeutic targets. By providing insights into the intricate interplay between Tregs and the TME, this review strives to stimulate further investigation and facilitate the development of targeted Treg-based therapeutic strategies for GC.

Transforming growth factor (TGF)-β1, a member of the TGF-β superfamily, is produced by many immune and nonimmune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T-cell differentiation and function. Consistently, loss of TGF-β1 function is associated with exacerbated T-cell-dependent inflammatory responses that culminate in pathological processes in allergic and immune-mediated diseases. In this review, we highlight the roles of TGF-β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)-17, and Th9 cells, thus contributing to amplifying or restricting T-cell responses in health and human diseases (e.g., inflammatory bowel diseases, type 1 diabetes, asthma, and MS). In addition, we discuss the involvement of Smad7, an inhibitor of TGF-β1 signaling, in immune-mediated disorders (e.g., psoriasis, rheumatoid arthritis, MS, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors.

Currently, immunotherapy targeting programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) has revolutionized the treatment strategy of human cancer patients. Meanwhile, PD-1/PD-L1 pathway has also been implicated in the pathogenesis of many immune-related diseases, such as autoimmune diseases, chronic infection diseases and adverse pregnancy outcomes, by regulating components of the innate and adaptive immune systems. Given the power of the new therapy, a better understanding of the regulatory effects of PD-1/PD-L1 pathway on innate and adaptive immune responses in immune-related diseases will facilitate the discovery of novel biomarkers and therapeutic drug targets. Targeting this pathway may successfully halt or potentially even reverse these pathological processes. In this review, we discuss recent major advances in PD-1/PD-L1 axis regulating innate and adaptive immune components in immune-related diseases. We reveal that the impact of PD-1/PD-L1 axis on the immune system is complex and manifold and multi-strategies on the targeted PD-1/PD-L1 axis are taken in the treatment of immune-related diseases. Consequently, targeting PD-1/PD-L1 pathway, alone or in combination with other treatments, may represent a novel strategy for future therapeutic intervention on immune-related diseases.