Effective Immunotherapy Research Articles

Clinical Practice Guideline: Immunotherapy for Inhalant Allergy.

Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AITis administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. The purpose of this clinical practice guideline (CPG) is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce the risk of harm.The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. The GDG made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients'symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitizations, (2) reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions (LRs) to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The GDG offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.

Identification of ferroptosis-related subtypes, characteristics of TME infiltration and development of prognostic models in gastric cancer

BackgroundFerroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. MethodsFRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. ResultsIn the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). ConclusionLow FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.

Changes in the Expression of Proteins Associated with Neurodegeneration in the Brains of Mice after Infection with Influenza A Virus with Wild Type and Truncated NS1.

Influenza type A virus (IAV) infection is a major cause of morbidity and mortality during influenza epidemics. Recently, a specific link between IAV infection and neurodegenerative disease progression has been established. The non-structural NS1 protein of IAV regulates viral replication during infection and antagonizes host antiviral responses, contributing to influenza virulence. In the present study, we have prepared a mouse lung-to-lung adapted to the NS1-truncated virus (NS80ad). Transcriptome analysis of the gene expression in the lungs revealed that infection with wild-type A/WSN/33 (WSN), NS80, and NS80ad viruses resulted in different regulation of genes involved in signaling pathways associated with the cell proliferation, inflammatory response, and development of neurodegenerative diseases. NS1 protein did not influence the genes involved in the RIG-I-like receptor signaling pathway in the brains. Lethal infection with IAVs dysregulated expression of proteins associated with the development of neurodegenerative diseases (CX3CL1/Fractalkine, Coagulation factor III, and CD105/Endoglin, CD54/ICAM-1, insulin-like growth factor-binding protein (IGFBP)-2, IGFBP-5, IGFBP-6, chitinase 3-like 1 (CHI3L1), Myeloperoxidase (MPO), Osteopontin (OPN), cystatin C, and LDL R). Transcription of GATA3 mRNA was decreased, and expression of MPO was inhibited in the brain infected with NS80 and NS80ad viruses. In addition, the truncation of NS1 protein led to reduced expression of IGFBP-2, CHI3L1, MPO, and LDL-R proteins in the brains. Our results indicate that the influenza virus influences the expression of proteins involved in brain function, and this might occur mostly through the NS1 protein. These findings suggest that the abovementioned proteins represent a promising target for the development of potentially effective immunotherapy against neurodegeneration.

From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer.

Lung cancer is a disease of global concern, and immunotherapy has brought lung cancer therapy to a new era. Besides promising effects in the clinical use of immune checkpoint inhibitors, immune-related adverse events (irAEs) and low response rates are problems unsolved. Natural products and traditional medicine with an immune-modulating nature have the property to influence immune checkpoint expression and can improve immunotherapy's effect with relatively low toxicity. This review summarizes currently approved immunotherapy and the current mechanisms known to regulate immune checkpoint expression in lung cancer. It lists natural products and traditional medicine capable of influencing immune checkpoints or synergizing with immunotherapy in lung cancer, exploring both their effects and underlying mechanisms. Future research on immune checkpoint modulation and immunotherapy combination applying natural products and traditional medicine will be based on a deeper understanding of their mechanisms regulating immune checkpoints. Continued exploration of natural products and traditional medicine holds the potential to enhance the efficacy and reduce the adverse reactions of immunotherapy.

CXCR5+TIM-3-PD-1+ stem-like cytotoxic CD8+ T cells: elevated in chronic rhinosinusitis and associated with disease severity.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease with an autoimmune background. Altered expression levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3), C-X-C chemokine receptor type 5 (CXCR5), and programmed cell death protein 1 (PD-1) are implicated in the progression of inflammatory and autoimmune diseases. Moreover, CXCR5+TIM-3-PD-1+ stem-like cytotoxic T cells function as memory stem cells during chronic disease processes and retain cytotoxicity-related gene networks. To explore the expressions of CXCR5, TIM-3, and PD-1 on T cells and their correlation with clinical parameters in CRS. Flow cytometry was used to assess the expressions and co-expressions of CXCR5, TIM-3, and PD-1 on T cells in the tissues of the paranasal sinus and peripheral blood of patients with CRS as well as healthy controls. Immunofluorescence was used to assess the co-localization of TIM-3, CXCR5, and PD-1 with T cells. The disease severity of our patients with CRS was evaluated using the Lund-Mackay score. A complete blood count was also performed for the patients with CRS. Expression levels of CXCR5 and PD-1 on T cells were significantly increased in the nasal tissues of patients with CRS. Compared with those in healthy controls, patients with CRS had high percentages of CXCR5+TIM-3-PD-1+ CD8+ and CD4+ T cells in nasal tissues, while no significant difference was observed in peripheral blood levels. Patients with CRS had a higher density of nasal CXCR5+TIM-3-PD-1+ T cells than that in healthy controls. CXCR5+TIM-3-PD-1+ CD8+ T cell levels in the nasal polyps of patients with CRS were negatively correlated with the patients' Lund-Mackay scores. The levels of CXCR5+TIM-3-PD-1+ T cells in nasal tissues were also negatively associated with disease duration and positively associated with the chronic inflammatory state of CRS. The level of CXCR5+TIM-3-PD-1+ stem cell-like T cells, especially CXCR5+TIM-3-PD-1+ CD8+ T cells, is increased in CRS. Therefore, inducing CXCR5+TIM-3-PD-1+ T cell exhaustion may be an effective immunotherapy for CRS.

A Triple-Responsive Polymeric Prodrug Nanoplatform with Extracellular ROS Consumption and Intracellular H2O2 Self-Generation for Imaging-Guided Tumor Chemo-Ferroptosis-Immunotherapy.

High reactive oxygen species (ROS) levels in tumor microenvironment (TME) impair both immunogenic cell death (ICD) efficacy and T cell activity. Furthermore, tumor escapes immunosurveillance via programmed death-1/programmed death ligand-1 (PD-L1) signal, and the insufficient intracellular hydrogen peroxide weakens ferroptosis efficacy. To tackle the above issues, a glutathione (GSH)/ROS/pH triple-responsive prodrug nanomedicine that encapsulates Fe2O3 nanoparticle via electrostatic interaction is constructed for magnetic resonance imaging (MRI)-guided multi-mode theranostics with chemotherapy/ferroptosis/immunotherapy. The diselenide bond consumes ROS in TME to increase T cells and ICD efficacy, the cleavage of which facilitates PD-L1 antagonist D peptide release to block immune checkpoint. After intracellular internalization, Fe2O3 nanoparticle is released in the acidic endosome for MRI simultaneously with lipid peroxides generation for tumor ferroptosis. Doxorubicin is cleaved from polymers in the condition of high intracellular GSH level accompanied by tumor ICD, which simultaneously potentiates ferroptosis by NADPH oxidase mediated H2O2 self-generation. In vivo results indicate that the nanoplatform strengthens tumor ICD, induces cytotoxic T lymphocytes proliferation, inhibits 4T1 tumor regression and metastasis, and prolongs survival median. In all, a new strategy is proposed in strengthening ICD and T cells activity cascade with ferroptosis as well as immune checkpoint blockade for effective tumor immunotherapy.

Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors.

Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

Artificial Intelligence for Precision Oncology of Triple-Negative Breast Cancer: Learning from Melanoma.

Thanks to new technologies using artificial intelligence (AI) and machine learning, it is possible to use large amounts of data to try to extract information that can be used for personalized medicine. The great challenge of the future is, on the one hand, to acquire masses of biological data that nowadays are still limited and, on the other hand, to develop innovative strategies to extract information that can then be used for the development of predictive models. From this perspective, we discuss these aspects in the context of triple-negative breast cancer, a tumor where a specific treatment is still lacking and new therapies, such as immunotherapy, are under investigation. Since immunotherapy is already in use for other tumors such as melanoma, we discuss the strengths and weaknesses identified in the use of immunotherapy with melanoma to try to find more successful strategies. It is precisely in this context that AI and predictive tools can be extremely valuable. Therefore, the discoveries and advancements in immunotherapy for melanoma provide a foundation for developing effective immunotherapies for triple-negative breast cancer. Shared principles, such as immune system activation, checkpoint inhibitors, and personalized treatment, can be applied to TNBC to improve patient outcomes and offer new hope for those with aggressive, hard-to-treat breast cancer.

B10 cells: Development, phenotype, and function in cancer.

B10 cells, a specialized subset of regulatory B cells, have been identified in both mice and humans. These cells are characterized by their regulatory impact on immune dynamics, principally through their secretion of interleukin-10 (IL-10), a cytokine known for its anti-inflammatory properties. The pivotal role of immune mediators such as B10 cells is to maintain a delicate equilibrium between antitumor immunity and tumor-promoting responses. Emerging studies have cast B10 cells as key suppressors in the antitumor immune arsenal. They operate in synergy with a spectrum of immune cells within the innate and adaptive spectrums, contributing to a milieu that favors tumor progression and metastatic spread. In this comprehensive review, we will discuss the ontogeny, phenotype and effector functions of B10 cells in murine systems. We will also review the role of B10 cells in oncological models in animal studies and extend these findings to the human clinical context, elucidating their role in facilitating tumor immune evasion. A thorough understanding of these processes is imperative for the strategic targeting and attenuation of B10 cell activity, which is anticipated to be a cornerstone in the advancement of effective cancer immunotherapy strategies.

Abstract B046: Exploring the potential of commensal polyomavirus as a promising approach for breast cancer treatment

Abstract Cancer is a leading cause of mortality worldwide, accounting for nearly one in six deaths. Our understanding of the immune system role in cancer control has increased dramatically in recent decades, facilitating the recent development of effective cancer immunotherapies, which have significantly improved the survival of cancer patients. However, current immunotherapies can induce overactive immune responses with severe even fatal outcomes. Moreover, immunotherapy may not work in every scenario, especially in ‘cold’ tumors that lack immune cell infiltration. Thus, more effective immunotherapies with fewer side effects are under active investigation. Viruses are one of the most abundant biological entities in the world; about 12% to 20% of human cancers are associated with viral infections. Viral antigens can increase tumor immunogenicity, triggering T cell immunity against tumor cells. Polyomaviruses are small, nonenveloped double-stranded DNA viruses that are widespread. In immunocompetent hosts, polyomaviruses remain at a low persistent level in the host after the primary infection, which appears to cause little or no symptoms. Previous studies have shown high polyomavirus seroprevalence and the frequent presence of polyomavirus-specific T cells in healthy adult blood donors. In the elderly population, Merkel cell polyomavirus (MCPyV) infection is linked to Merkel cell carcinoma (MCC), a rare, aggressive skin cancer associated with immunosuppression. MCPyV integration into the genome is the primary oncogenic event in ~80% of MCC cases, and the remaining virus-negative MCC cases are associated with ultraviolet (UV) radiation. MCPyV-induced MCCs are associated with more intratumor immune cells and better responses to cancer therapy. Moreover, BK and JC polyomavirus positive lymphoma patients showed a trend toward significantly better overall survival. These clinical data suggest that polyomavirus in tumors may increase tumor immunogenicity. Thus, polyomavirus presents an intriguing opportunity to develop a novel strategy to enhance cancer immunogenicity. We utilized mouse polyomavirus (MPyV) to colonize typically ‘cold’ breast tumor cell line E0771 breast cancer cells in mice. MPyV infection blocked the growth of tumors in immunocompetent mice and promoted immune cell infiltration when intratumorally delivered to the tumor. The tumor rejection activity of polyomavirus is depend on CD4 and CD8 T cells. Unlike conventional oncolytic viruses which directly lyse the infected cells and trigger a nonspecific inflammatory response, polyomavirus does not lyse the colonized cells, and it induces a relatively low level of inflammation. Instead, polyomavirus stimulates viral antigen expression in tumors that boosts T cell response leading to epitope spreading to tumor-associated antigens. The outcomes of this research will establish the utility of commensal polyomavirus as a novel agent for cancer immunotherapy. Citation Format: YUN XIA. Exploring the potential of commensal polyomavirus as a promising approach for breast cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B046.

Impaired monocyte-derived dendritic cell phenotype in prostate cancer patients: A phenotypic comparison with healthy donors.

Dendritic cells (DCs) play a crucial role in immunity. Research on monocyte-derived DCs (Mo-DCs) cancer vaccines is in progress despite limited success in clinical trials. This study focuses on Mo-DCs generated from prostate cancer (PCA) patients, comparing them with DCs from healthy donors (HD-DCs). Mo-DCs were isolated from PCA patient samples, and their phenotype was compared to HD-DCs. Key parameters included monocyte count, CD14 expression, and the levels of maturation markers (HLA-DR, CD80, CD86) were assessed. PCA samples exhibited a significantly lower monocyte count and reduced CD14 expression compared to healthy samples (p ⟨ 0.0001). Additionally, PCA-DCs expressed significantly lower levels of maturation markers, including HLA-DR, CD80, and CD86, when compared to HD-DCs (p = 0.123, p = 0.884, and p = 0.309, respectively). The limited success of DC vaccines could be attributed to impaired phenotypic characteristics. These observations suggest that suboptimal characteristics of Mo-DCs generated from cancer patient blood samples might contribute to the limited success of DC vaccines. Consequently, this study underscores the need for alternative strategies to enhance the features of Mo-DCs for more effective cancer immunotherapies.

Single-cell landscape identifies the immunophenotypes and microenvironments of HBV-positive and HBV-negative liver cancer.

HBV infection leads to HCC and affects immunotherapy. We are exploring the tumor ecosystem in HCC to help gain a deeper understanding and design more effective immunotherapy strategies for patients with HCC with or without HBV infection. Single-cell RNA sequencing series were integrated as a discovery cohort to interrogate the tumor microenvironment of HBV-positive (HBV+) HCC and HBV-negative (HBV-) HCC. We further dissect the intratumoral immune status of HBV+ HCC and HBV- HCC. An independent cohort, including samples treated with immune checkpoint blockade therapy, was used to validate the major finding and investigate the effect of HBV infection on response to immunotherapy. The interrogation of tumor microenvironment indicated that regulatory T cells, exhausted CD8+ T cells, and M1-like Macrophage_MMP9 were enriched in HBV+ HCC, while mucosa-associated invariant T cells were enriched in HBV- HCC. All subclusters of T cells showed high expression of immune checkpoint genes in HBV+ HCC. Regulatory T cells enriched in HBV+ HCC also showed more robust immunosuppressive properties, which was confirmed by cross talk between immune cell subsets. The ability of antigen presentation with major histocompatibility complex-II was downregulated in HBV+ HCC and this phenomenon can be reversed by immunotherapy. Two types of HCC also present different responses to immunotherapy. There is a more immunosuppressive and exhausted tumor microenvironment in HBV+ HCC than in HBV- HCC. This in-depth immunophenotyping strategy is critical to understanding the impact of HBV and the HCC immune microenvironment and helping develop more effective treatments in patients with HCC.

Characterization of hypoxia-responsive states in ovarian cancer to identify hot tumors and aid adjuvant therapy

BackgroundsThe hypoxia-responsive state of cancer is a complex pathophysiological process involving numerous genes playing different roles. Due to the rapid proliferation of cancer cells and chaotic angiogenesis, the clinical features of hypoxia-responsive states are not yet clear in patients with ovarian cancer.MethodsBased on the RNA expression levels of 14 hypoxic markers, our study screened out hypoxia-related genes and construct a hypoxic score pattern to quantify the hypoxia-responsive states of a single tumor. Combining clinical prognosis, tumor mutation burden, microsatellite instability, the expression level of the immune checkpoint, IC50, and other indicators to evaluate the impact of different hypoxia-responsive states on clinical prognosis and therapeutic sensitivity.ResultsOur study identified a subgroup with an active hypoxia-responsive state and they have a worse clinical prognosis but exhibit higher immunogenicity and higher sensitivity to immunotherapy.ConclusionsThis work revealed that hypoxia-responsive states played an important role in formation of tumor immunogenicity. Evaluating the hypoxia-responsive state will contribute to guiding more effective immunotherapy strategies.

Synergistic Viro-chemoimmunotherapy in Breast Cancer Enabled by Bioengineered Immunostimulatory Exosomes and Dual-Targeted Coxsackievirus B3.

Breast cancer's immunosuppressive environment hinders effective immunotherapy, but oncolytic viruses hold promise for addressing this challenge by targeting tumor cells and altering the microenvironment. Yet, neutralizing antibodies and immune clearance impede their clinical utility. This study explored microRNA-modified coxsackievirus B3 (miR-CVB3), an innovative oncolytic virus, and its potential in breast cancer treatment. It investigated miR-CVB3's impact on immune-related proteins and utilized exosomes as both protective shields and delivery carriers. Results demonstrated miR-CVB3's capacity to reshape immune-related protein profiles toward a more immunostimulatory state and enhance exosome-mediated immune cell activation. Notably, cancer cell-released exosomes encapsulating miR-CVB3 (ExomiR-CVB3) maintained its antitumor cytotoxicity and bolstered its immunostimulatory effects. Moreover, ExomiR-CVB3 shielded miR-CVB3 from neutralizing antibodies and rapid immune clearance when it was systemically administered. Building on these findings, ExomiR-CVB3 was engineered with the AS1411 aptamer and doxorubicin (ExomiR-CVB3/DoxApt), enhancing therapeutic efficacy. This notable approach, combining genomic modification, aptamer surface decoration, and doxorubicin addition, demonstrated safe delivery of CVB3 to cancer cells. Comprehensive in vitro and in vivo analyses revealed selective breast cancer cell targeting, cell death induction, and significant immune cell infiltration within the tumor microenvironment while sparing healthy organs. In summary, this study highlights ExomiR-CVB3/DoxApt as a pioneering breast cancer treatment strategy adaptable for diverse cancer types, offering a potent and versatile approach to reshaping cancer immunotherapy.

GRANZYME A-PRODUCING CD4 T CELLS ARE DRIVERS OF IMMUNE CHECKPOINT BLOCKADE-INDUCED COLITIS

Abstract Immune checkpoint blockade (ICB) (i.e. anti-CTLA4 and/or anti-PD-1) is a type of cancer immunotherapy that is broadly and effectively used across multiple cancer types. Despite this efficacy, ~60% of individuals of ICB recipients develop autoimmune-like inflammation in the skin, lungs and intestines. Of these barrier sites, an inflamed intestine is the most common form of severe disease that requires cessation of immunotherapy and potential tumor rebound. ICB-induced colitis therefore represents a significant health concern in an increasing population of cancer patients receiving this otherwise effective immunotherapy. Previous work has shown evidence of a dysregulated intestinal CD4 T cell response in ICB colitis patients, however, how CD4 T cells might contribute to disease has remained unclear. Here, we identify a unique subset of T helper (Th) 1-like CD4 T cells that express the serine protease granzyme A (GZMA) that are specifically elevated in ICB-induced colitis patients, suggesting a pathogenic role for GZMA-expressing Th cells in disease. As mouse models for ICB-induced colitis are virtually non-existent, we have profiled existing mouse models of intestinal inflammation for the presence of colonic GZMA-expressing CD4 T cells for more in-depth functional studies. Using this approach, we have identified the T cell transfer model of colitis as a model that mimics the GZMA CD4 T cell phenotype observed in human ICB colitis patients. Within this model, GZMA-expressing CD4 T cells arise early in the intestines after transfer and only minimally express other CD4 T helper (Th) cell lineage cytokines (i.e. IFN-γ or IL-17) indicating that these cells may represent a unique Th cell subtype that are associated with intestinal disease. Indeed, transfer of GZMA-deficient CD4 T cells into colitis-prone mice resulted in reduced intestinal inflammation and damage, despite efficient trafficking of these cells to the intestines. Mechanistically, CD4 T cell-derived GZMA promoted an exaggerated intestinal epithelial cell response to the microbiota, but was not required for immune-editing of the microbiota in this setting. Taken together, our data indicate that GZMA-producing Th cells are likely major contributors to ICB-induced colitis and may represent a valuable therapeutic target for limiting intestinal disease during ICB therapy.

Multi-omics comprehensive analyses of programmed cell death patterns to regulate the immune characteristics of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer with high morbidity and mortality. Triggering the programmed cell death (PCD) to enhance the anti-tumor therapies is being applied in multiple cancers. However, the limited understanding of genetic heterogeneity in HNSCC severely hampers the clinical efficacy. We systematically analyzed 14 types of PCD in HNSCC from The Cancer Genome Atlas (TCGA). We utilized ssGSEA to calculate the PCD scores and classify patients into two clusters. Subsequently, we displayed the genomic alteration landscape to unravel the significant differences in copy number alterations and gene mutations. Furthermore, we calculated the IC50 values of targeted drugs to predict the differences in sensitivity. To identify the immune-related prognostic types, we comprehensively estimated the relationship between immune indicators and all prognostic PCD in three datasets (TCGA, GSE65858, GSE41613). Finally, 7 regulators were filtered. Subsequently, we integrated 10 machine learning algorithms and 101 algorithm combinations to test the clinical predictive efficacy. Using WGCNA as a basis, we built a weighted co-expression network to identify modules involved in the immune landscape with different colors. Meanwhile, our results indicated that blue and red modules containing crucial regulators closely related to the CD4+, CD8+ T cells, TMB or PD-L1. FCGR2A from blue module, CSF2, INHBA, and THBS1 from the red module were determined. After verifying in vivo experiments, FCGR2A was identified as hub gene. In conclusion, our findings suggest a potential role of PCD in HNSCC, offering new insights into effective immunotherapy and anti-tumor therapies in HNSCC.

Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. Statement of significanceThe limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.

Nanoscale Metal-Organic Frameworks-Mediated Degradation of Mutant p53 Proteins and Activation of cGAS-STING Pathway for Enhanced Cancer Immunotherapy.

Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Glioma: bridging the tumor microenvironment, patient immune profiles and novel personalized immunotherapy.

Glioma is the most common primary brain tumor, characterized by a consistently high patient mortality rate and a dismal prognosis affecting both survival and quality of life. Substantial evidence underscores the vital role of the immune system in eradicating tumors effectively and preventing metastasis, underscoring the importance of cancer immunotherapy which could potentially address the challenges in glioma therapy. Although glioma immunotherapies have shown promise in preclinical and early-phase clinical trials, they face specific limitations and challenges that have hindered their success in further phase III trials. Resistance to therapy has been a major challenge across many experimental approaches, and as of now, no immunotherapies have been approved. In addition, there are several other limitations facing glioma immunotherapy in clinical trials, such as high intra- and inter-tumoral heterogeneity, an inherently immunosuppressive microenvironment, the unique tissue-specific interactions between the central nervous system and the peripheral immune system, the existence of the blood-brain barrier, which is a physical barrier to drug delivery, and the immunosuppressive effects of standard therapy. Therefore, in this review, we delve into several challenges that need to be addressed to achieve boosted immunotherapy against gliomas. First, we discuss the hurdles posed by the glioma microenvironment, particularly its primary cellular inhabitants, in particular tumor-associated microglia and macrophages (TAMs), and myeloid cells, which represent a significant barrier to effective immunotherapy. Here we emphasize the impact of inducing immunogenic cell death (ICD) on the migration of Th17 cells into the tumor microenvironment, converting it into an immunologically "hot" environment and enhancing the effectiveness of ongoing immunotherapy. Next, we address the challenge associated with the accurate identification and characterization of the primary immune profiles of gliomas, and their implications for patient prognosis, which can facilitate the selection of personalized treatment regimens and predict the patient's response to immunotherapy. Finally, we explore a prospective approach to developing highly personalized vaccination strategies against gliomas, based on the search for patient-specific neoantigens. All the pertinent challenges discussed in this review will serve as a compass for future developments in immunotherapeutic strategies against gliomas, paving the way for upcoming preclinical and clinical research endeavors.

Integrated multi-omics analyses reveal the TM4SF family genes with prognostic and therapeutic relevance in hepatocellular carcinoma.

TM4SF family members (TM4SFs) have been shown to be aberrantly expressed in multiple types of cancer. However, a comprehensive investigation of the TM4SFs has yet to be performed in LIHC. The study comprehensively investigated the expression and prognostic value of TM4SFs. Then, a TM4SFs-based risk model and nomogram were constructed for prognostic prediction. Finally, functional loss of TM4SFs was performed to verify the potential role of TM4SFs in LIHC. We found that TM4SFs were significantly up-regulated in LIHC. High expression and hypomethylation of TM4SFs were associated with poor prognosis of LIHC patients. Then, a TM4SFs-based risk model was constructed that could effectively classify LIHC patients into high and low-risk groups. In addition, we constructed a prognostic nomogram that could predict the long-term survival of LIHC patients. Based on immune infiltration analysis, high-risk patients had a relatively higher immune status than low-risk patients. Moreover, the prediction module could predict patient responses to immunotherapy and chemotherapy. Finally, loss-of-function studies showed that TM4SF4 knockdown could substantially suppress the growth, migratory, and invasive abilities of LIHC cells. Targeting TM4SFs will contribute to effective immunotherapy strategies and improve the prognosis of liver cancer patients.