Target For Immunotherapy Research Articles

SET facilitates immune escape of microsatellite stability colorectal cancer by inhibiting c-Myc degradation.

Microsatellite stability (MSS) colorectal cancer (CRC) exhibits a low mutation load and poor immunogenicity, contributing to immune escape of tumor cells and less benefit from immune checkpoint blockade (ICB) treatment. The mechanisms underlying immunotherapeutic resistance in MSS CRC remain to be elucidated. Here, we identified that nuclear proto-oncogene SET is significantly higher expressed in MSS CRC compared to microsatellite instability (MSI) CRC and facilitates immune escape of MSS CRC. Mechanistically, SET represses the expression of C-C motif chemokine ligand 5 (CCL5) and upregulates mismatch repair (MMR) proteins expression in a c-Myc-dependent manner, which inhibits infiltration and migration of CD8+ T cells to tumor tissues and results in low immunogenicity in MSS CRC. In addition, we found that SET impairs ubiquitination and proteasomal degradation of c-Myc by disrupting the interaction between E3 ligase FBXW7 and c-Myc. Moreover, SET inhibition enhances the response to immunotherapy in MSS CRC invivo. Overall, this study reveals the critical roles and posttranslational regulatory mechanism of SET in immune escape and highlights the SET/c-Myc axis as a potential target for immunotherapy of MSS CRC that have implications for targeting a unique aspect of this disease.

In silico and pharmacological evaluation of GPR65 as a cancer immunotherapy target regulating T-cell functions.

The success of cancer immunotherapies such as immune checkpoint inhibitors, CAR T-cells and immune cell engagers have provided clinicians with tools to bypass some of the limitations of cancer immunity. However, numerous tumour factors curtail the immune response against cancer and limit the efficiency of immuno-oncology (IO) therapies. Acidification of the extra-cellular tumour environment consecutive to aberrant cancer cell metabolism is a well-known promoter of oncogenic processes that also acts as an immune regulator. Yet, the suppressive mechanisms of low extra-cellular pH on anti-cancer immunity remain poorly understood. Recent reports have suggested that GPR65, a Gαs-coupled proton-sensing GPCR broadly expressed in the immune system, may act as an immune suppressant detrimental to anti-tumour immunity. So far, the immuno-regulatory properties of GPR65 in acidic milieux have mostly been documented in macrophages and myeloid cells. Our computational evaluation of GPR65's transcriptomic expression profile and potential as an IO target using public datasets prompted us to further investigate its functions in human T-cells. To this end, we identified and validated GPR65 small molecule inhibitors active in in vitro cellular assays and we showed that GPR65 inhibition promoted the killing capacity of antigen-specific human T-cells. Our results broaden the scope of GPR65 as an IO target by suggesting that its inhibition may enhance T-cell anti-tumour activity and provide useful pharmacological tools to further investigate the therapeutic potential of GPR65 inhibition.

Assessment of anti-CD69 antibody therapy alone or in combination with anti-PD-1 in murine GBM

ABSTRACT Background Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model. Research design and methods CD69 expression in GBM patient tissues was analyzed using the TCGA database. Therapeutic efficacy of anti-CD69 was tested in a murine GBM model with different regimens. Immune cell populations in the tumor microenvironment (TME) were assessed by flow cytometry. Results Increased CD69 expression was observed in GBM patients compared to normal brain tissue and was associated with worse prognosis. Anti-CD69 treatment reduced percentages of CD69+ immune cells but did not improve survival in GBM-bearing mice. Increased PD-1 expression on NK cells was observed following anti-CD69 treatment. Anti-CD69 treatment was not improved by the addition of anti-PD-1 in vivo. Conclusions This is the first study evaluating anti-CD69 therapy in a preclinical GBM model. Despite promising preclinical data in other cancers, anti-CD69 monotherapy or combination therapy with anti-PD-1 did not improve survival in this GBM model.

Targeting the LMP1-ALIX axis in EBV+ nasopharyngeal carcinoma inhibits immunosuppressive small extracellular vesicle secretion and boosts anti-tumor immunity.

Immunotherapy has revolutionized the therapeutical regimen for nasopharyngeal carcinoma (NPC), yet its response rate remains insufficient. Programmed death-ligand 1 (PD-L1) on small extracellular vesicles (sEVs) mediates local and peripheral immunosuppression in tumors, and the mechanism of PD-L1 loading into these vesicles is garnering increasing attention. Latent membrane protein 1 (LMP1), a key viral oncoprotein expressed in Epstein-Barr virus (EBV)-positive NPC, contributes to remodeling the tumor microenvironment. However, the precise mechanisms by which LMP1 modulates tumor immunity in NPC remain unclear. Here, we aimed to investigate the roles and regulatory mechanisms of LMP1 and sEV PD-L1 in NPC immune evasion. We analyzed the impact of LMP1 on tumor-infiltrating lymphocyte abundance in NPC tissues and humanized tumor-bearing mouse models using multiplex immunofluorescence (mIF) and flow cytometry, respectively. Transmission electron microscopy and nanoparticle tracking analysis were employed to characterize sEVs. Immunoprecipitation-mass spectrometry was utilized to identify proteins interacting with LMP1. The regulatory effects of sEVs on tumor microenvironment were assessed by monitoring CD8+ T cell proliferation and interferon-γ (IFN-γ) expression via flow cytometry. Furthermore, the expression patterns of LMP1 and downstream regulators in NPC were analyzed using mIF and survival analysis. High LMP1 expression in NPC patient specimens and mouse models was associated with restricted infiltration of CD8+ T cells. Additionally, LMP1 promoted sEV PD-L1 secretion, leading to inhibition of CD8+ T cell viability and IFN-γ expression in vitro. Mechanistically, LMP1 recruited apoptosis-linked gene 2-interacting protein X (ALIX) through its intracellular domain and bound PD-L1 through its transmembrane domain, thereby facilitating the loading of PD-L1 into ALIX-dependent sEVs. Disruption of ALIX diminished LMP1-induced sEV PD-L1 secretion and enhanced the anti-tumor immunity of CD8+ T cells both in vitro and in vivo. Moreover, increased expression levels of LMP1 and ALIX were positively correlated with enhanced immunosuppressive features and worse prognostic outcomes in NPC patients. Our findings uncovered the mechanism by which LMP1 interacts with ALIX and PD-L1 to form a trimolecular complex, facilitating PD-L1 loading into ALIX-dependent sEV secretion pathway, ultimately inhibiting the anti-tumor immune response in NPC. This highlights a novel target and prognostic marker for NPC immunotherapy.

IL-17A-producing γδ T cells: A novel target in stroke immunotherapy.

The activation of the immune system is crucial for the fate of the ischemic brain tissue and neurological outcome in experimental stroke. Rapidly after stroke γδ (γδ17), T cells release IL-17A in the ischemic brain and thereby amplify the early detrimental immune response. Notably, IL-17A levels in γδ17 T cells are modulated by the intestinal microbiota which is, in turn, shaped by the diet. Importantly, besides their proinflammatory effects, meningeal γδ17 T cells have been recently implicated in regulating neuronal signaling, behavior, and cognition under homeostatic and pathological conditions at the brain-meningeal interface. Against this background, we propose that a dietary intervention represents a promising treatment option to improve poststroke outcomes by the modulation of the microbiota composition and IL-17A levels in γδ T cells.

Recent advancement of immunotherapy targeting lung cancer

As one of the leading cause of deaths in all types of cancer, lung cancer has attracted public attention more than decades. Many chemotherapy and physical surgery therapies have been investigated and applied to lung cancer patients to increase the overall survival rate. As a more recently emerging therapy, immunotherapy is keep advancing in recent years and has achieved great success to complement the traditional therapys weak point and even become the first line treatment against certain types of non-small cell lung cancer (NSCLC). The safety and overall survival improvement of immunotherapy drugs has been tested through multiple cycle of clinical trials, validating their potential for lung cancer treatment. Several clinical trials study the application of immunotherapy singly or in combination with chemotherapy has been established to target lung cancer many years ago. Here, this review will introduce the three most common immunotherapies against lung cancer, and both summarize their application and discuss their recent advancement based on multiple ongoing or finished clinical trials.

LncRNA SNHG16 Inhibits Intracellular M. tuberculosis Growth Involving Cathelicidin Pathway, Autophagy, and Effector Cytokines Production.

Long noncoding small nucleolar RNA (LncRNA) host gene 16 (SNHG16) is associated with certain diseases, including cancers. However, its role and mechanism in Mycobacterium tuberculosis (Mtb) infection remain unclear. Here, we demonstrated that SNHG16 expression levels were suppressed in peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes of tuberculosis (TB) patients. SNHG16 was up-regulated by acute Mtb infection of PBMCs from healthy control (HC) subjects. Such TB suppression of SNHG16 was consistent with an immunosuppressive-like state driven by IL-10 signaling as seen in TB patients. Notably, SNHG16 limited Mtb growth in macrophages/monocytes through autophagy and vitamin D receptor (VDR)-dependent cathelicidin (CAMP) antimicrobial pathways. Concurrently, SNHG16 was highly expressed in lymphocytes, including CD8+ and Vγ2 Vδ2 T-cell subsets in HCs. SNHG16 overexpression in lymphocytes allowed them to control Mtb infection in macrophages, and SNHG16 epigenetically increased the expression of anti-Mtb effector cytokines in lymphocytes by developing more accessible chromatin states in gene loci encoding IFN-γ, TNF-α, and Granzyme B. Furthermore, the adoptive transfer of SNHG16-overexpressing human PBMCs into Mtb-infected SCID mice conferred protective immunity against Mtb infection. Thus, SNHG16 drove the induction of pleiotropic effector functions that inhibited intracellular Mtb growth in vitro and in vivo, serving as an immunotherapy target in TB.

Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (T1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

Sustained Clinical Benefit and Intracranial Activity of Tarlatamab in Previously Treated Small Cell Lung Cancer: DeLLphi-300 Trial Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Hypoxia-related lncRNA correlates with prognosis and immune microenvironment in uveal melanoma

BackgroundHypoxia-related genes are linked to the prognosis of various solid malignant tumors. However, the role of hypoxia-related long non-coding RNAs (HRLs) in uveal melanoma (UVM) remains unclear. This study aimed to identify HRLs associated with UVM prognosis and develop a novel risk signature to predict patient outcomes.MethodsData from 80 UVM samples were obtained from The Cancer Genome Atlas. Prognostic HRLs were screened using Cox univariate and Pearson correlation analyses. HRL signature were constructed using Lasso analysis, and gene enrichment analysis was performed to explore the association between HRLs and immune features. Cell Counting Kit-8 assay was used to measure the propagation of human uveal melanoma (MuM2B) cells, while tumor invasion and migration were evaluated using Transwell and wound-healing experiments. Inflammatory factors and macrophage polarization were evaluated using quantitative PCR.ResultsIn total, 621 prognostic HRLs were screened and constructed in 12 HRLs. The risk score showed a significant correlation with the survival time of patients with UVM. Additionally, HRL correlated with diverse key immune checkpoints, revealing possible targets for immunotherapy. Immune-related pathways were highly enriched in the high-risk group. LINC02367, a protective HRL, was associated with the tumor microenvironment and survival time of patients with UVM. In vitro, LINC02367 significantly influenced MuM2B proliferation and migration. It also modulated macrophage polarization by regulating inflammatory factor levels, thereby affecting the immune microenvironment.ConclusionsWe developed a novel HRL signature to predict prognosis in patients with UVM. HRLs are potential biomarkers and therapeutic targets for the treatment of UVM.

Exploring the role of ADAMTSL2 across multiple cancer types: A pan-cancer analysis and validated in colorectal cancer

BackgroundRecent studies have established a correlation between ADAMTSL2 (ADAMTS-like 2) and the development of various cancers. This study aims to conduct a comprehensive pan-cancer analysis in 37 cancer types and investigate its potential role in colon and rectal adenocarcinoma (COADREAD).MethodPan-cancer and mutation data were sourced from The Cancer Genome Atlas (TCGA) database and analyzed using Sangerbox analysis platform. We explored the expression patterns and prognostic implications of ADAMTSL2, and investigated its relationships with tumor heterogeneity, stemness, immune checkpoint genes, immune cell infiltration, RNA modifications, and mutational profiles across different cancers. Additionally, with Ethics Committee approval, we conducted immunohistochemical (IHC) analysis on 120 COADEAD samples to evaluate ADAMTSL2 expression and its association with clinicopathological parameters.ResultsADAMTSL2 expression was positively correlated with the hazard ratio of OS, DSS, DFI and PFI for ESCA and COADREAD. A negative correlation was observed between ADAMTSL2 expression and NEO levels in COAD. Gene alterations in ADAMTSL2 were observed, with a mutation frequency of 5.0% in COAD. There is a significant correlation between ADAMTSL2 expression and immune cell infiltration in a variety of cancers. The expression level of ADAMTSL2 protein was associated with T stage, N stage, M stage (p < 0.05). Kaplan‒Meier survival curves demonstrated that the high ADAMTSL2 group had a shorter OS time (p = 0.047) and progression free survival time (p = 0.026) than the low ADAMTSL2 group.ConclusionIn summary, we conducted a comprehensive pan-cancer analysis of ADAMTSL2 and we demonstrated that ADAMTSL2 may serve as a novel prognostic biomarker and immunotherapy target in COADREAD.

Causal role of 731 immune cells in diabetic nephropathy: a bi-directional two-sample Mendelian randomization study.

The primary cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN), and a growing body of research indicates that immunology plays a part in how DN develops into ESRD. Our objective is to identify causal relationships between various immune invading cells and DN to identify possible targets for immunotherapy. This study used a complete Mendelian randomization (MR) analysis with two samples to identify the underlying mechanism linking immune cell characteristics with DN. Using publicly available genetic data, we investigated the causal link between 731 immune cell profiles and DN risk. Included were four different types of immune systems: morphological parameters (MP), absolute cell (AC), relative cell (RC), and median fluorescence intensities (MFI). The results' robustness, heterogeneity, and horizontal pleiotropy were confirmed through extensive sensitivity analysis. Following FDR (False Discovery Rate correction method) correction, no statistically significant differences were observed; however, six immunophenotypes were shown to be significantly associated with DN risk at the 0.25 level. Only CD28+ CD4- CD8- T cells were identified as the protective immunophenotype (OR = 0.588, 95% CI 0.437-0.792, P = 4.71 × 10-4). Moreover, DN had no discernible impact on immunophenotyping after FDR correction. Surprisingly, three unadjusted phenotypes with low P values were discovered to be positively correlated with the risk of DN: CD20 on IgD- CD27- B cells (OR = 1.263, 95% CI 1.076-1.482, P = 4.22 × 10-3), CD8 on naive CD8 + T cells with Effector Memory (OR = 1.107, 95% CI 1.013-1.209, P = 2.40 × 10-2), and CD8 on Effector Memory CD8 + T cells (OR = 1.126, 95% CI 1.024-1.239, P = 1.46 × 10-2). Our findings provide a genetic basis for the association between immune cells and DN and should inform future clinical research.

FANCA promotes lung adenocarcinoma progression and is a potential target for epitope vaccine immunotherapy

BackgroundFANCA mutations have been detected in a variety of cancers and found to be pro-carcinogenic. However, no functional studies have been identified regarding the involvement of FANCA in the occurrence and the immune response of LUAD.MethodsThe mRNA expression and overall survival rates of FANCA were evaluated by the TIMER, PrognoScan and TCGA database in LUAD tissues, and FANCA expression was further validated by clinical serum samples using ELISA. The correlation between FANCA and immune infiltration level was investigated via TISIDB database and CIBERSORT algorithm. The Kaplan–Meier plotter was used to further evaluate the prognostic value based on the expression levels of FANCA in related immune cells. Then, the influence of FANCA knockout on the proliferation, migration, and invasion of A549 and H1299 cells was validated using CCK8, cloning formation, and Transwell assays. Subsequently, HLA-A2-restricted FANCA antigenic peptides were predicted and synthesized by NetMHC4.0 and SYFPEITHI, and DCs were induced and cultured in vitro. Finally, DCs loaded with HLA-A2-restricted FANCA antigenic peptides were co-cultured with autologous peripheral blood lymphocyte to generate specific CTLs. The killing effects of different CTLs on LUAD cells were studied.ResultsThe results showed that high levels of FANCA in patients with LUAD were significantly correlated with worse OS survival, which was correlated with age, clinical stage, pathological T stage, M stage, and N stage in LUAD. Knockdown of FANCA in A549 and H1299 cells significantly inhibited proliferation, metastasis, and invasion in vitro. In addition, FANCA was significantly related to immune infiltrate, genomic alterations and TMB. FANCA expression infuenced the prognosis of LUAD patients by directly affecting immune cell infltration. Finally, HLA-A2-restricted FANCA antigenic peptides were synthesized. And FANCA 146–154 (SLLEFAQYL) antigenic peptide exhibit a stronger affinity for DCs, and induce CTLs to produce stronger targeted killing ability for LUAD cells at an effector-to-target ratio of 40:1.ConclusionThese results demonstrated that the elevation of FANCA promotes malignant phenotype of LUAD, and the potential peptide P2 (SLLEFAQYL) derived from FANCA may be used as an epitope vaccine for the treatment of LUAD.

Neudesin regulates dendritic cell function and antitumor CD8+ T cell immunity

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

VSIG-3/IGSF11 silencing in A2058 melanoma cells simultaneously suppresses melanoma progression and induces anti-tumoral cytokine profile in human T cells: In silico and in vitro study.

VISTA is a newly discovered immune checkpoint whose functional mechanisms have become increasingly important to study due to its brilliant results in cancer immunotherapy. Despite VSIG-3/IGSF11 being identified as an inhibitory ligand for VISTA with potential as a target for cancer immunotherapy, very little is known of its functions. This study aimed to conduct a detailed analysis of VSIG-3/IGSF11 in melanoma, as well as to study the effects of its silencing on melanoma cell line progression and human T cell functions. Online databases were used to investigate VSIG-3/IGSF11 expression, its relationships, and prognostic value in melanoma. Then, the effects of VSIG-3/IGSF11 silencing on proliferation, migration, cell cycle arrest, and apoptosis in A2058 melanoma cells were assessed using MTT, colony formation, wound healing, cell cycle, and Annexin-VFITC/PI assays, respectively. Finally, A2058 cells transfected with VSIG-3/IGSF11 siRNA were co-cultured with human T cells, and the expression levels of T cell cytokines were evaluated using qRT-PCR. VSIG-3/IGSF11 expression was significantly increased in melanoma patients and cell lines; however, no correlation was found between VSIG-3/IGSF11 expression levels and clinicopathological characteristics, survival, or immune cell infiltration. Following VSIG-3/IGSF11 silencing in A2058 cells, viability, proliferation, and migration rates were decreased, while apoptosis was increased. T cells co-cultured with VSIG-3/IGSF11 siRNA-transfected A2058 cells exhibited increased expression levels of IFN-γ and IL-12 and decreased expression levels of IL-10, TGF-β, and TNF-α. The inhibitory effect of VSIG-3/IGSF11 silencing on A2058 melanoma cell progression, along with the alteration of T cell cytokines towards a pro-inflammatory phenotype, suggests that VSIG-3/IGSF11 is primarily involved in melanoma progression and modulating immune responses. Therefore, it may be a valuable target for immunotherapy in melanoma patients.

Targeting CD276 for T cell-based immunotherapy of breast cancer.

Breast cancer (BC) is the most common malignancy in women. Immunotherapy has revolutionized treatment options in many malignancies, and the introduction of immune checkpoint inhibition yielded beneficial results also in BC. However, many BC patients are ineligible for this T cell-based therapy, others do not respond or only briefly. Thus, there remains a high medical need for new therapies, particularly for triple-negative BC. CD276 (B7-H3) is overexpressed in several tumors on both tumor cells and tumor vessels, constituting a promising target for immunotherapy. We analyzed tumor samples of 25 patients using immunohistochemistry to assess CD276 levels. The potential of CC-3, a novel bispecific CD276xCD3 antibody, for BC treatment was evaluated using various functional in vitro assays. Pronounced expression of CD276 was observed in all analyzed tumor samples including triple negative BC. In analyses with BC cells, CC-3 induced profound T cell activation, proliferation, and T cell memory subset formation. Moreover, treatment with CC-3 induced cytokine secretion and potent tumor cell lysis. Our findings characterize CD276 as promising target and preclinically document the therapeutic potential of CC-3 for BC treatment, providing a strong rationale for evaluation of CC-3 in BC patients in a clinical trial for which the recruitment has recently started.

PRAME expression in fibrosarcomatous dermatofibrosarcoma protuberans

PRAME (PReferentially expressed Antigen in MElanoma) was first identified as a malignant melanoma-specific antigen. Recently, a few cases of fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) were shown to have positivity for PRAME, while conventional dermatofibrosarcoma protuberans (C-DFSP) was negative. Because PRAME may be of diagnostic utility in FS-DFSP and is raising expectations as a new immunotherapy target, we examined the positivity of PRAME in FS-DFSP. Twenty-one cases of FS-DFSP and age/sex/location-matched cases of C-DFSP as a control group were examined by immunohistochemistry for CD34 and PRAME. The results were then evaluated by H-score, which was objectively and semi-quantitatively calculated using the open-source bioimaging analysis software QuPath. The results revealed that the PRAME H-score in FS-DFSP was significantly higher than that in C-DFSP (p = 0.0137). As for CD34, the H-score in FS-DFSP was significantly lower than that in C-DFSP (p < 0.001). Using these two immunohistochemical analyses in combination, the sensitivity and specificity for the diagnosis of FS-DFSP were 86% and 90%, respectively. Double staining of CD34 and PRAME revealed that PRAME-positive and CD34-positive areas did not overlap. This is the largest study to examine PRAME expression in FS-DFSP, and it confirmed the usefulness of PRAME in diagnosing this condition.

DeepNeoAG: Neoantigen epitope prediction from melanoma antigens using a synergistic deep learning model combining protein language models and multi-window scanning convolutional neural networks

Neoantigens, derived from tumor-specific mutations, play a crucial role in eliciting anti-tumor immune responses and have emerged as promising targets for personalized cancer immunotherapy. Accurately identifying neoantigens from a vast pool of potential candidates is crucial for developing effective therapeutic strategies. This study presents a novel deep learning model that leverages the power of protein language models (PLMs) and multi-window scanning convolutional neural networks (CNNs) to predict neoantigens from normal tumor antigens with high accuracy. In this study, we present DeepNeoAG, a novel framework combines the global sequence-level information captured by a pre-trained PLM with the local sequence-based information features extracted by a multi-window scanning CNN, enabling a comprehensive representation of the protein's mutational landscape. We demonstrate the superior performance of DeepNeoAG compared to existing methods and highlight its potential to accelerate the development of personalized cancer immunotherapies.

Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects.

The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant to traditional therapies. This scholarly review examines the diverse categories of STING agonists, encompassing CDN analogues, non-CDN chemotypes, CDN-infused exosomes, engineered bacterial vectors, and hybrid structures of small molecules-nucleic acids. We highlight their mechanisms, clinical trial progress, and therapeutic outcomes. While these agents offer significant promise, challenges such as toxicity, tumor heterogeneity, and delivery methods remain obstacles to their broader clinical use. Ongoing research and innovation are essential to overcoming these hurdles. STING agonists could play a transformative role in cancer treatment, particularly for patients with hard-to-treat malignancies, by harnessing the body's immune system to target and eliminate cancer cells.

A proteomic atlas of glypican‐3 interacting partners: Identification of alpha‐fetoprotein and other extracellular proteins as potential immunotherapy targets in liver cancer

AbstractAntibody and cell‐based therapeutics targeting cell surface receptors have emerged as a major class of immune therapeutics for treating cancer. However, the number of cell surface targets for cancer immunotherapy remains limited. Glypican‐3 (GPC3) is a cell surface proteoglycan and an oncofetal antigen. In this study, we report a large‐scale tumor‐associated GPC3 co‐immunoprecipitation‐proteomic study using liver cancer xenograft tumors in mice. We identified 153 GPC3‐associated proteins through mass spectrometry. To identify potential drug targets, we categorized GPC3‐associated proteins based on their subcellular locations using UniProt annotations, with a focus on extracellular proteins. Additionally, we annotated differentially expressed proteins in hepatocellular carcinoma versus nontumor liver samples based on the literature, analyzed expression levels in tumor versus normal tissues using TCGA and GTEx databases via GEPIA, and identified prognostic liver cancer markers according to GEPIA. Among GPC3‐associated proteins, immunoglobulin superfamily member 1, alpha‐fetoprotein (AFP), FAT atypical cadherin 1, formin 1, and guanylate cyclase 2 C, were identified as potential therapeutic targets. Furthermore, we validated the direct protein interaction between GPC3 and AFP through immunoprecipitation with purified proteins and through co‐localization imaging using immunofluorescence microscopy. This study provides large proteomic datasets related to GPC3‐associated proteins, enhancing our understanding of glypican biology in cancer cells and offering a new approach to identifying immunotherapy targets.