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Background: Redirection of T lymphocytes against tumor antigens can induce dramatic regression of advanced stage malignancy. The use of bispecific antibodies (BsAbs) that bind both the T-cell receptor (TCR) and a target antigen is one promising approach to T-cell redirection. However, BsAbs indiscriminately bind all CD3+ T-cells and trigger TCR activation in the absence of parallel costimulatory signals required to overcome T-cell unresponsiveness or anergy., Methods: To address these limitations, a combination platform was designed wherein a unique BsAb referred to as frBsAb exclusively engages T-cells engineered to express a novel chimeric receptor comprised of extracellular folate receptor fused to intracellular TCR and CD28 costimulatory signaling domains in tandem; a BsAb-binding immune receptor (BsAb-IR). As a surrogate TCR, the BsAb-IR allows for concomitant TCR and costimulatory signaling exclusively in transduced T-cells upon engagement with specific frBsAbs, and can therefore redirect T-cells on command to desired antigen. Human primary T-cells were transduced with lentiviral vector and expanded for 14-18 days. BsAb-IRs were harvested and armed with frBsAbs to test for redirected cytotoxicity against CD20 positive cancer cell lines., Results: Using frBsAbs specific for CD20 or HER2, the lytic activity of primary human T-cells expressing the BsAb-IR was specifically redirected against CD20+ leukemic cells or HER2+ epithelial cancer cells, respectively, while non-engineered T-cells were not activated. Notably, elimination of the CD28 costimulatory domain from the BsAb-IR construct significantly reduced frBsAb-redirected antitumor responses, confirming that frBsAbs are capable of delivering simultaneous TCR activation and costimulatory signals to BsAb-IR T-cells., Conclusion: In summary, our results establish the proof of concept that the combination of BsAbs with optimized gene-engineered T-cells provides the opportunity to specify and augment tumor antigen-specific T-cell activation and may improve upon the early success of conventional BsAbs in cancer immunotherapy.

Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy. [ABSTRACT FROM AUTHOR]

CD8+ T cells are the workhorses executing adaptive anti-tumour response, and targets of various cancer immunotherapies. Latest advances have unearthed the sheer heterogeneity of CD8+ tumour infiltrating lymphocytes, and made it increasingly clear that the bulk of the endogenous and therapeutically induced tumour-suppressive momentum hinges on a particular selection of CD8+ T cells with advantageous attributes, namely the memory and stem-like exhausted subsets. A scrutiny of the contemporary perception of CD8+ T cells in cancer and the subgroups of interest along with the factors arbitrating their infiltration contextures, presented herein, may serve as the groundwork for future endeavours to probe further into the regulatory networks underlying their differentiation and migration, and optimise T cell-based immunotherapies accordingly. [ABSTRACT FROM AUTHOR]

Background: The small non-coding microRNAs play an important role in development by regulating protein translation, but their involvement in axon guidance is unknown. Here, we investigated the role of microRNA-134 (miR-134) in chemotropic guidance of nerve growth cones., Results: We found that miR-134 is highly expressed in the neural tube of Xenopus embryos. Fluorescent in situ hybridization also showed that miR-134 is enriched in the growth cones of Xenopus spinal neurons in culture. Importantly, overexpression of miR-134 mimics or antisense inhibitors blocked protein synthesis (PS)-dependent attractive responses of Xenopus growth cones to a gradient of brain-derived neurotrophic factor (BDNF). However, miR-134 mimics or inhibitors had no effect on PS-independent bidirectional responses of Xenopus growth cones to bone morphogenic protein 7 (BMP7). Our data further showed that Xenopus LIM kinase 1 (Xlimk1) mRNA is a potential target of miR-134 regulation., Conclusions: These findings demonstrate a role for miR-134 in translation-dependent guidance of nerve growth cones. Different guidance cues may act through distinct signaling pathways to elicit PS-dependent and -independent mechanisms to steer growth cones in response to a wide array of spatiotemporal cues during development.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD. [ABSTRACT FROM AUTHOR]

Tumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC. [ABSTRACT FROM AUTHOR]

Background: Emerging investigations have increasingly highlighted the critical role of tumor-associated macrophages (TAMs) and M2 macrophages in cancer development, progression, and metastasis, marking them as potential targets in various cancer types. The main objective of this research is to discover new biomarkers associated with TAM-M2 macrophages in colorectal cancer (CRC) and to dissect the molecular heterogeneity of CRC by combining single-cell RNA sequencing and bulk RNA-seq data. Methods: By utilizing weighted gene co-expression network analysis (WGCNA), we acquired TAM-M2-associated genes by intersecting TAM marker genes obtained from scRNA-seq data with module genes of M2 macrophages derived from bulk RNA-seq data. We employed least absolute shrinkage and selection operator (LASSO) Cox analysis to select predictive biomarkers from these TAM-M2-related genes. Quantitative polymerase chain reaction (qPCR) was employed to validate the mRNA expression levels of the genes identified in the screening. This led to the development of the TAM-M2-related signature (TAMM2RS). We also conducted functional and immune landscape analyses of different risk groups. Results: The combination of scRNA-seq and bulk RNA-seq analyses yielded 377 TAM-M2-related genes. DAPK1, NAGK, and TRAF1 emerged as key prognostic genes in CRC, which were identified through LASSO Cox analysis. Utilizing these genes, we constructed and validated the TAMM2RS, demonstrating its effectiveness in predicting survival in CRC patients. Conclusion: Our research offers a thorough investigation into the molecular mechanisms associated with TAM-M2 macrophages in CRC and unveils potential therapeutic targets, offering new insights for treatment strategies in colorectal cancer. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy has revolutionized cancer treatment, especially for hematologic malignancies. T cells are the most extensively utilized cells in adoptive cell therapy. Currently, tumor-infiltrating lymphocytes, T cell receptor-transgenic T cells and chimeric antigen receptor T cells are the three main adoptive T cell therapies. Tumor-infiltrating lymphocytes kill tumors by reinfusing enlarged lymphocytes that naturally target tumor-specific antigens into the patient. T cell receptor-transgenic T cells have the ability to specifically destroy tumor cells via the precise recognition of exogenous T cell receptors with major histocompatibility complex. Chimeric antigen receptor T cells transfer genes with specific antigen recognition structural domains and T cell activation signals into T cells, allowing T cells to attack tumors without the assistance of major histocompatibility complex. Many barriers have been demonstrated to affect the clinical efficacy of adoptive T cell therapy, such as tumor heterogeneity and antigen loss, hard trafficking and infiltration, immunosuppressive tumor microenvironment and T cell exhaustion. Several strategies to improve the efficacy of adoptive T cell therapy have been explored, including multispecific chimeric antigen receptor T cell therapy, combination with immune checkpoint blockade, targeting the immunosuppressive tumor microenvironment, etc. In this review, we will summarize the current status and clinical application, followed by major bottlenecks in adoptive T cell therapy. In addition, we will discuss the promising strategies to improve adoptive T cell therapy. Adoptive T cell therapy will result in even more incredible advancements in solid tumors if the aforementioned problems can be handled. [ABSTRACT FROM AUTHOR]

Background: Molecular subtyping is expected to enable precise treatment. However, reliable subtyping strategies for clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE), we aimed to develop a novel TIDE-based subtyping strategy to guide personalized immunotherapy in the bladder cancer (BC). Methods: Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. Subsequently, consensus clustering was applied to classify BC patients based on TIDE marker-genes. Patients' clinicopathological, molecular features and signaling pathways of the different TIDE subtypes were well characterized. We also utilize the deconvolution algorithms to analyze the tumor microenvironment, and further explore the sensitivity and mechanisms of each subtype to immunotherapy. Furthermore, BC patient clinical information, real-world BC samples and urine samples were collected for the validation of our findings, which were used for RNA-seq analysis, H&E staining, immunohistochemistry and immunofluorescence staining, and enzyme-linked immunosorbent assay. Finally, we also explored the conservation of our novel TIDE subtypes in pan-cancers. Results: We identified 69 TIDE biomarker genes and classified BC samples into three subtypes using consensus clustering. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples and collected patient clinical data. This subtyping method was proved to be more efficient than previous known methods in identifying non-responders to immunotherapy. We also propose that combining our TIDE subtypes with known biomarkers can potentially improve the sensitivity and specificity of these biomarkers. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, we confirmed that the TIDE subtypes are conserved across the pan-tumors. Conclusions: Our novel TIDE-based subtyping method can serve as a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized therapy decisions for selecting potential beneficiaries and excluding resistant patients of ICB therapy. [ABSTRACT FROM AUTHOR]

The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors. [ABSTRACT FROM AUTHOR]

T cells are fundamental components in tumour immunity and cancer immunotherapies, which have made immense strides and revolutionized cancer treatment paradigm. However, recent studies delineate the predicament of T cell dysregulation in tumour microenvironment and the compromised efficacy of cancer immunotherapies. CRISPR screens enable unbiased interrogation of gene function in T cells and have revealed functional determinators, genetic regulatory networks, and intercellular interactions in T cell life cycle, thereby providing opportunities to revamp cancer immunotherapies. In this review, we briefly described the central roles of T cells in successful cancer immunotherapies, comprehensively summarised the studies of CRISPR screens in T cells, elaborated resultant master genes that control T cell activation, proliferation, fate determination, effector function, and exhaustion, and highlighted genes (BATF, PRDM1, and TOX) and signalling cascades (JAK-STAT and NF-κB pathways) that extensively engage in multiple branches of T cell responses. In conclusion, this review bridged the gap between discovering element genes to a specific process of T cell activities and apprehending these genes in the global T cell life cycle, deepened the understanding of T cell biology in tumour immunity, and outlined CRISPR screens resources that might facilitate the development and implementation of cancer immunotherapies in the clinic. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor-T (CAR-T) cells therapy is one of the novel immunotherapeutic approaches with significant clinical success. However, their applications are limited because of long preparation time, high cost, and interpersonal variations. Although the manufacture of universal CAR-T (U-CAR-T) cells have significantly improved, they are still not a stable and unified cell bank. Methods: Here, we tried to further improve the convenience and flexibility of U-CAR-T cells by constructing novel modular universal CAR-T (MU-CAR-T) cells. For this purpose, we initially screened healthy donors and cultured their T cells to obtain a higher proportion of stem cell-like memory T (TSCM) cells, which exhibit robust self-renewal capacity, sustainability and cytotoxicity. To reduce the alloreactivity, the T cells were further edited by double knockout of the T cell receptor (TCR) and class I human leukocyte antigen (HLA-I) genes utilizing the CRISPR/Cas9 system. The well-growing and genetically stable universal cells carrying the CAR-moiety were then stored as a stable and unified cell bank. Subsequently, the SDcatcher/GVoptiTag system, which generate an isopeptide bond, was used to covalently connect the purified scFvs of antibody targeting different antigens to the recovered CAR-T cells. Results: The resulting CAR-T cells can perform different functions by specifically targeting various cells, such as the eradication of human immunodeficiency virus type 1 (HIV-1)-latenly-infected cells or elimination of T lymphoma cells, with similar efficiency as the traditional CAR-T cells did. Conclusion: Taken together, our strategy allows the production of CAR-T cells more modularization, and makes the quality control and pharmaceutic manufacture of CAR-T cells more feasible. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Macrophages and tumour stroma cells account for the main cellular components in the tumour microenvironment (TME). Current advancements in single-cell analysis have revolutionized our understanding of macrophage diversity and macrophage–stroma interactions. Accordingly, this review describes new insight into tumour-associated macrophage (TAM) heterogeneity in terms of tumour type, phenotype, metabolism, and spatial distribution and presents the association between these factors and TAM functional states. Meanwhile, we focus on the immunomodulatory feature of TAMs and highlight the tumour-promoting effect of macrophage–tumour stroma interactions in the immunosuppressive TME. Finally, we summarize recent studies investigating macrophage-targeted therapy and discuss their therapeutic potential in improving immunotherapy by alleviating immunosuppression. [ABSTRACT FROM AUTHOR]

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR). As an adaptive cellular response to hostile microenvironments, such as hypoxia, nutrient deprivation, oxidative stress, and chemotherapeutic drugs, the UPR is activated in diverse cancer types and functions as a dynamic tumour promoter in cancer development; this role of the UPR indicates that regulation of the UPR can be utilized as a target for tumour treatment. T-cell exhaustion mainly refers to effector T cells losing their effector functions and expressing inhibitory receptors, leading to tumour immune evasion and the loss of tumour control. Emerging evidence suggests that the UPR plays a crucial role in T-cell exhaustion, immune evasion, and resistance to immunotherapy. In this review, we summarize the molecular basis of UPR activation, the effect of the UPR on immune evasion, the emerging mechanisms of the UPR in chemotherapy and immunotherapy resistance, and agents that target the UPR for tumour therapeutics. An understanding of the role of the UPR in immune evasion and therapeutic resistance will be helpful to identify new therapeutic modalities for cancer treatment. 3hLdj6N9ZZbWsv-inx3vFn Video Abstract [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T cells have shown significant activity in B-lineage malignancies. However, their efficacy in myeloid leukemia has not been successful due to unclear molecular mechanisms. Methods: We conducted in vitro and in vivo experiments to investigate whether myeloid leukemia cells directly induce CAR down-regulation. Furthermore, we designed a CD33 CARKR in which all lysines in the cytoplasmic domain of CAR were mutated to arginine and verified through in vitro experiments that it could reduce the down-regulation of surface CARs and enhance the killing ability. Transcriptome sequencing was performed on various AML and ALL cell lines and primary samples, and the galectin-1-specific inhibitory peptide (anginex) successfully rescued the killing defect and T-cell activation in in vitro assays. Results: CAR down-regulation induced by myeloid leukemia cells under conditions of low effector-to-tumor ratio, which in turn impairs the cytotoxicity of CAR T cells. In contrast, lysosomal degradation or actin polymerization inhibitors can effectively alleviate CAR down-regulation and restore CAR T cell-mediated anti-tumor functions. In addition, this study identified galectin-1 as a critical factor used by myeloid leukemia cells to induce CAR down-regulation, resulting in impaired T-cell activation. Conclusion: The discovery of the role of galectin-1 in cell surface CAR down-regulation provides important insights for developing strategies to restore anti-tumor functions. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies. [ABSTRACT FROM AUTHOR]

Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. Methods: 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher's exact test were applied to test for group differences. Results: A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. Conclusion: These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations. [ABSTRACT FROM AUTHOR]

Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as clinical benefit is only available for a fraction of patients. A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice. Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design, guide gene-based T cell modification, and optimize the CAR-T manufacturing conditions, and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes. The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities. In this review, we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies. We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy. Specifically, we provide an overview of single-cell studies focusing on target antigens, CAR-transgene integration, and preclinical research and clinical applications, and then discuss how it will affect the future of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Background: Botox injections are commonly used for cosmetic and therapeutic purposes because they temporarily paralyze muscles, reduce wrinkles, and alleviate certain medical conditions. Although generally considered safe and effective, Botox injections may cause potential complications. While herpes reactivation is more commonly associated with immunosuppressive therapies, such as chemotherapy or corticosteroid use, its association with Botox injection is poorly documented. Case Presentation: A 33-year-old woman presented with progressive painful rashes and vesicles on her forehead, scalp, and right upper eyelid, accompanied by fever and malaise following a Botox injection to treat wrinkles. A positive Tzanck smear test result confirmed the diagnosis of herpes infection. The patient was treated with antiviral medication, and her symptoms gradually regressed over several days. Conclusions: Although herpes reactivation is more commonly associated with immunosuppressive therapies, few cases of herpes zoster and herpes simplex following Botox injection have been reported. The pathogenesis of herpes reactivation following Botox injection is unclear; however, it has been hypothesized that the Botox protein is a potent antigen that may activate the cellular immune system, making it easier for the virus to reactivate. Healthcare providers should be aware of this potential complication and consider it when evaluating patients who present with painful rashes following Botox injections. In addition, individuals who want to receive Botox injections should be informed of this complication. The diagnosis of herpetic infection should be made promptly, and antiviral therapy should be initiated to minimize the risk of complications. Further research is needed to better understand the pathogenesis and risk factors for herpes following Botox injection and to develop strategies for preventing and managing this complication. [ABSTRACT FROM AUTHOR]

Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed. Key points: 1) Established the computational process and platform of neoantigen prediction, and comprehensive prediction and screening of tumor specific neoantigens. 2) Rapid identification of neoantigen-specific TCRs for personalized engineered TCR-T cell therapy. 3) Classification and characteristics of tumor specific neoantigen-based therapy, and combined antitumor strategies. 4) The current status, inherent challenges, and clinical translational potential of TCR-T therapy. [ABSTRACT FROM AUTHOR]

Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants—namely, melanoma, colon, glioma, and breast cancers. [ABSTRACT FROM AUTHOR]

Background: The receptor tyrosine kinases TAM family (TYRO3, AXL, and MERTK) are highly expressed in multiple forms of cancer cells and tumor-associated macrophages and promote the development of cancers including pancreatic tumor. Targeting TAM receptors could be a promising therapeutic option. Methods: We designed a novel CAR based on the extracellular domain of growth arrest-specific protein 6 (GAS6), a natural ligand for all TAM members. The ability of CAR-T to kill pancreatic cancer cells is tested in vitro and in vivo, and the safety is evaluated in mice and nonhuman primate. Results: GAS6-CAR-T cells efficiently kill TAM-positive pancreatic cancer cell lines, gemcitabine-resistant cancer cells, and cancer stem-like cells in vitro. GAS6-CAR-T cells also significantly suppressed the growth of PANC1 xenografts and patient-derived xenografts in mice. Furthermore, these CAR-T cells did not induce obvious side effects in nonhuman primate or mice although the CAR was demonstrated to recognize mouse TAM. Conclusions: Our findings indicate that GAS6-CAR-T-cell therapy may be effective for pancreatic cancers with low toxicity. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor therapy has revolutionized the clinical management of a diverse range of cancer types, including advanced cutaneous melanoma. While immunotherapy targeting the PD-1/PD-L1 system has become standard of care, overall response rates remain unsatisfactory for most patients and there are no approved small molecule inhibitors of the PD-1/PD-L1 system. Flubendazole (FLU) is an anthelmintic that has been used to treat worm infections in humans and animals for decades. Methods: Here we tested the anti-cancer activity of systemically delivered FLU with suppression of PD-1 in immunocompetent mice. Results: In C57BL/6J mice bearing subcutaneous B16F10 melanoma, FLU reduced both tumor growth and PD-1 protein levels without affecting levels of PD-L1. FLU's suppression of PD-1 was accompanied by increased CD3+ T cell infiltration. Western blotting with extracts from human Jurkat T cells showed that FLU inhibited PD-1 protein expression, findings confirmed by flow cytometry. To gain mechanistic insights on FLU's ability to suppress PD-1 protein levels, we performed bulk RNA sequencing on extracts of Jurkat T cells exposed to the benzimidazole for 4 h. From a pool of 14,475 genes there were 1218 differentially-expressed genes; 687 with increased expression and 531 with decreased expression. Among the genes induced by FLU was the AP-1 family member, JUN and surprisingly, pdcd1. KEGG pathway analysis showed FLU up-regulated genes over-represented in multiple pathways (p < 0.01), the top hit being amoebiasis. FLU also affected the expression of genes in cancer-associated pathways, both through down-regulation and up-regulation. Gene set enrichment analysis revealed a large number of immunological signature gene sets correlated with FLU treatment, including gene sets associated with T cell differentiation, proliferation and function. The AP-1 inhibitor T5224 rescued PD-1 protein expression from inhibition by FLU. Conclusion: This study is the first to show that FLU can inhibit melanoma growth with PD-1 suppression in immunocompetent mice. [ABSTRACT FROM AUTHOR]

The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases. [ABSTRACT FROM AUTHOR]

The most common kind of acute leukemia in adults is acute myeloid leukemia (AML), which is often treated with induction chemotherapy regimens followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT). However, some patients continue to develop relapsed or refractory AML (R/R-AML). Small molecular targeted drugs require long-time administration. Not all the patients hold molecular targets. Novel medicines are therefore needed to enhance treatment outcomes. T cells and natural killer (NK) cells engineered with chimeric antigen receptors (CARs) that target antigens associated with AML have recently been produced and are currently being tested in both pre-clinical and clinical settings. This review provides an overview of CAR-T/NK treatments for AML. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

In recent years, tumor immunotherapy has made significant progress. However, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), benefits only a tiny proportion of patients in solid cancers. The tumor microenvironment (TME) acts a significant role in tumor immunotherapy. Studies reported that tumor-associated macrophages (TAMs), as one of the main components of TME, seriously affected the therapeutic effect of PD-1/PD-L1 inhibitors. In this review, we analyzed TAMs from epigenetic and single-cell perspectives and introduced the role and mechanisms of TAMs in anti-programmed death protein 1(anti-PD-1) therapy. In addition, we summarized combination regimens that enhance the efficacy of tumor PD-1/PD-L1 inhibitors and elaborated on the role of the TAMs in different solid cancers. Eventually, the clinical value of TAMs by influencing the therapeutic effect of tumor PD-1/PD-L1 inhibitors was discussed. These above are beneficial to elucidate poor therapeutic effect of PD-1/PD-L1 inhibitors in solid tumors from the point of view of TAMs and explore the strategies to improve its objective remission rate of solid cancers. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) genomics is an emerging discipline that studies the three-dimensional structure of chromatin and the three-dimensional and functions of genomes. It mainly studies the three-dimensional conformation and functional regulation of intranuclear genomes, such as DNA replication, DNA recombination, genome folding, gene expression regulation, transcription factor regulation mechanism, and the maintenance of three-dimensional conformation of genomes. Self-chromosomal conformation capture (3C) technology has been developed, and 3D genomics and related fields have developed rapidly. In addition, chromatin interaction analysis techniques developed by 3C technologies, such as paired-end tag sequencing (ChIA-PET) and whole-genome chromosome conformation capture (Hi-C), enable scientists to further study the relationship between chromatin conformation and gene regulation in different species. Thus, the spatial conformation of plant, animal, and microbial genomes, transcriptional regulation mechanisms, interaction patterns of chromosomes, and the formation mechanism of spatiotemporal specificity of genomes are revealed. With the help of new experimental technologies, the identification of key genes and signal pathways related to life activities and diseases is sustaining the rapid development of life science, agriculture, and medicine. In this paper, the concept and development of 3D genomics and its application in agricultural science, life science, and medicine are introduced, which provides a theoretical basis for the study of biological life processes. [ABSTRACT FROM AUTHOR]

In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However, both show limited efficacies in most solid neoplasms, which necessitates the exploration of new immunotherapeutic modalities. The failure of CAR-T and immune checkpoint blockade in several solid neoplasms is attributed to multiple factors, including low antigenicity of tumor cells, low infiltration of effector T cells, and diverse mechanisms of immunosuppression in the tumor microenvironment. New adoptive cell therapies have been attempted for solid neoplasms, including TCR-T, CAR-natural killer cells (CAR-NK), and CAR-macrophages (CAR-M). Compared to CAR-T, these new adoptive cell therapies have certain advantages in treating solid neoplasms. In this review, we summarized the 40-year evolution of adoptive cell therapies, then focused on the advances of TCR-T, CAR-NK, and CAR-M in solid neoplasms and discussed their potential clinical applications. [ABSTRACT FROM AUTHOR]

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. Methods: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. Results: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. Conclusions: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: C-Jun, a critical component of AP-1, exerts essential functions in various tumors, including melanoma, and is believed to be a druggable target for cancer therapy. Unfortunately, no effective c-Jun inhibitors are currently approved for clinical use. The advent of immune checkpoint inhibitor (ICI) has brought a paradigm shift in melanoma therapy, but more than half of patients fail to exhibit clinical responses. The exploration of new combination therapies has become the current pursuit of melanoma treatment strategy. This study aims to screen out Chinese herbal monomers that can target c-Jun, explore the combined effect of c–Jun inhibitor and ICI, and further clarify the related molecular mechanism. Methods: We adopted a combinatorial screening strategy, including molecular docking, ligand-based online approaches and consensus quantitative structure-activity relationship (QSAR) model, to filter out c-Jun inhibitors from a traditional Chinese medicine (TCM) library. A mouse melanoma model was used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Multicolor flow cytometry was employed to assess the tumor microenvironment (TME). Multiple in vitro assays were performed to verify down-streaming signaling pathway. CD4 + T-cell differentiation assay was applied to investigate Treg differentiation in vitro. Results: Ailanthone (AIL) was screened out as a c-Jun inhibitor, and inhibited melanoma cell growth by directly targeting c-Jun and promoting its degradation. Surprisingly, AIL also facilitated the therapeutic efficacy of anti-programmed death ligand-1 (PD-L1) in melanoma cells by reducing the infiltration of Tregs in TME. Additionally, AIL treatment inhibited c-Jun-induced PD-L1 expression and secretion. As a consequence, Treg differentiation was attenuated after treatment with AIL through the c-Jun/PD-L1 axis. Conclusion: Our findings identified AIL as a novel c-Jun inhibitor, and revealed its previously unrecognized anti-melanoma effects and the vital role in regulating TME by Treg suppression, which provides a novel combination therapeutic strategy of c-Jun inhibition by AIL with ICI. AIL down-regulates c-Jun by reducing its stability, and inhibits the function of Tregs via AIL-c-Jun-PD-L1 pathway, ultimately suppressing melanoma progression and enhancing the efficacy of anti-PD-L1. [ABSTRACT FROM AUTHOR]

Strongylid and non-strongylid nematodes are one of the most important parasites infecting equines. The traditional method to identify these nematodes is through coproscopy and fecal culture. Because of the scarcity of data published in Egypt discussing the morphometric features of infective 3rd larvae of these nematodes, this study aims to provide a morphometric key for L3 of common strongylid and non-strongylid nematodes infecting Egyptian equines. For this reason, we cultured fecal samples containing GINs eggs and 3rd larval stages were identified based on their morphology (i.e., shape and number of intestinal cells (IC), shape of the esophagus, and shape of the tail sheath) in addition to computing their dimensions (i.e., length of larvae with sheath, length of the esophagus, length of intestinal cells, and body breadth). We identified 3rd larval stages of four strongylid nematodes (Cyathostomumsensulato, Strongylus vulgaris, Strongylus equinus, and Strongylus edentatus) as well as two non-strongylid nematodes (Strongyloides westeri, and Trichostrongylus axei). Statistically, our results revealed significant differences in terms of total length, body width, esophagus length, and gut length among 3rd larvae identified in the current study. The combination of both morphological and metric keys will allow the better identification of common strongylid and non-strongylid nematodes infecting equines. [ABSTRACT FROM AUTHOR]

Background: Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods: The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results: Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions: Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development. [ABSTRACT FROM AUTHOR]

In recent decades, the advent of immune-based therapies, most notably Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment. The promising results of numerous studies indicate that CAR-T cell therapy has had a remarkable ability and successful performance in treating blood cancers. However, the heterogeneity and immunosuppressive tumor microenvironment (TME) of solid tumors have challenged the effectiveness of these anti-tumor fighters by creating various barriers. Despite the promising results of this therapeutic approach, including tumor degradation and patient improvement, there are some concerns about the efficacy and safety of the widespread use of this treatment in the clinic. Complex and suppressing tumor microenvironment, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T cell exhaustion, and reduced cytotoxicity in the tumor site limit the applicability of CAR-T cell therapy and highlights the requiring to improve the performance of this treatment. With this in mind, in the last decade, many efforts have been made to use other treatments for cancer in combination with tuberculosis to increase the effectiveness of CAR-T cell therapy, especially in solid tumors. The combination therapy results have promising consequences for tumor regression and better cancer control compared to single therapies. Therefore, this study aimed to comprehensively discuss different cancer treatment methods in combination with CAR-T cell therapy and their therapeutic outcomes, which can be a helpful perspective for improving cancer treatment in the near future. [ABSTRACT FROM AUTHOR]

In the past decade, single-cell technologies have revealed the heterogeneity of the tumor-immune microenvironment at the genomic, transcriptomic, and proteomic levels and have furthered our understanding of the mechanisms of tumor development. Single-cell technologies have also been used to identify potential biomarkers. However, spatial information about the tumor-immune microenvironment such as cell locations and cell–cell interactomes is lost in these approaches. Recently, spatial multi-omics technologies have been used to study transcriptomes, proteomes, and metabolomes of tumor-immune microenvironments in several types of cancer, and the data obtained from these methods has been combined with immunohistochemistry and multiparameter analysis to yield markers of cancer progression. Here, we review numerous cutting-edge spatial 'omics techniques, their application to study of the tumor-immune microenvironment, and remaining technical challenges. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies' clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized. [ABSTRACT FROM AUTHOR]

Advancements in adoptive cell therapy over the last four decades have revealed various new therapeutic strategies, such as chimeric antigen receptors (CARs), which are dedicated immune cells that are engineered and administered to eliminate cancer cells. In this context, CAR T-cells have shown significant promise in the treatment of hematological malignancies. However, many obstacles limit the efficacy of CAR T-cell therapy in both solid tumors and hematological malignancies. Consequently, CAR-NK and CAR-M cell therapies have recently emerged as novel therapeutic options for addressing the challenges associated with CAR T-cell therapies. Currently, many CAR immune cell trials are underway in various human malignancies around the world to improve antitumor activity and reduce the toxicity of CAR immune cell therapy. This review will describe the comprehensive literature of recent findings on CAR immune cell therapy in a wide range of human malignancies, as well as the challenges that have emerged in recent years. [ABSTRACT FROM AUTHOR]

Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice. [ABSTRACT FROM AUTHOR]

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy. [ABSTRACT FROM AUTHOR]