Target For Immunotherapy Research Articles

Differential antibody response to EBV proteome following EBVST immunotherapy in EBV-associated lymphomas

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV-antigen specific antibody responses associated with clinical outcomes, we comprehensively characterized the antibody responses to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who received EBVST infusions enrolled in Phase I clinical trials. Responders (non-progressors) and non-responders (progressors) had distinct antibody profiles against EBV. Twenty-five IgG antibodies were significantly elevated in higher levels in non-responders compared to responders at 3 months post-EBVST infusion. Ten of these remained significant after adjustment for sex, age, and cancer type, including LMP2A (four variants), BGRF1/BDRF1 (two variants), LMP1, BKRF2, BKRF4, and BALF5. Random forest analysis identified these 10-IgG antibodies as key predictors of clinical response. Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our findings suggest that these EBV-directed antibodies as potential serological markers for predicting clinical responses to EBVST infusions and as therapeutic targets for immunotherapy in EBV-positive lymphomas. NCT01555892 - Cytotoxic T-Lymphocytes for EBV-positive Lymphoma, GRALE NCT02973113 - Nivolumab With Epstein Barr Virus Specific T Cells (EBVSTS), Relapsed/Refractory EBV Positive Lymphoma (PREVALE) NCT02287311 - Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1 And EBNA1 Specific CTL, EBV-Positive Lymphoma (MABEL)

Tumor-Intrinsic SIRPA Drives Pyroptosis Evasion in Head and Neck Cancer.

Pyroptosis, a gasdermin-mediated immunogenic cell death, has been shown to elicit adaptive antitumor immune responses, thereby augmenting the response to cancer immunotherapy when pyroptosis is therapeutically activated. However, despite increased gasdermin E (GSDME) expression, significant pyroptosis remains elusive in certain tumor types, and the underlying regulatory mechanisms are poorly understood. In this study, we observed high signal regulatory protein α1 (SIRPA) expression in head and neck squamous cell carcinoma (HNSCC) cells, a target in cancer immunotherapy. Intriguingly, SIRPA inhibition markedly augmented pyroptosis activity in tumor tissues and modulated tumor growth in a HNSCC mouse model. Subsequent investigations revealed that SIRPA knockout upregulated GSDME expression and potentiated cisplatin-induced pyroptosis in cancer cells. Integrative transcriptomics and metabolomics analysis suggested that the SIRPA knockout profoundly altered protein ubiquitination and augmented argininosuccinic acid levels in cancer cells. Specifically, we demonstrated that ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, targets GSDME for deubiquitination and that USP18 knockdown suppressed cisplatin-induced pyroptosis. Notably, we found that succinylation of GSDME, which is mediated by succinyl-CoA, promotes GSDME cleavage without affecting caspase-3 activation. Further experiments indicated that SIRPA expression in tumor cells can decrease the antitumor efficacy of chemotherapy and immunotherapy in HNSCC mouse models. In summary, our findings reveal a novel mechanism of pyroptosis evasion in HNSCC, whereby tumor-intrinsic SIRPA enhances GSDME ubiquitylation and inhibits its succinylation. These insights suggest that inhibiting SIRPA expression may improve the efficacy of immunotherapy for HNSCC by inducing pyroptosis.

Identifying potential signatures of immune cells in hepatocellular carcinoma using integrative bioinformatics approaches and machine-learning strategies.

Hepatocellular carcinoma (HCC) is a malignant tumor regulated by the immune system. Immunotherapy using checkpoint inhibitors has shown encouraging outcomes in a subset of HCC patients. The main challenges in checkpoint immunotherapy for HCC are to expand treatment options and to broaden the beneficiary population. Therefore, the search for potential signatures of immune cells is meaningful in the development of immunotherapy for HCC. The HCC related datasets were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Differential expression analysis and functional analysis were performed first. Then support vector machine-recursive feature elimination (SVM-RFE), random forests (RF), least absolute shrinkage and selection operation (LASSO), and weighed gene co-expression network analysis (WGCNA) were employed to screen for critical genes, and receiver operating characteristic (ROC) analysis was performed to compare diagnostic performance. Subsequently, single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between signatures and immune cells. Finally, we validated the expression of these biomarkers in human HCC samples. 531 overlapping differentially expressed genes (DEGs) were identified. Furthermore, enrichment analysis revealed pathways associated with immune activation processes, immune cell involvement and inflammatory signaling. After using multiple machine-learning strategies, extracellular matrix protein 1 (ECM1), leukemia inhibitory factor receptor (LIFR), sushi repeat containing protein X-linked (SRPX), and thromboxane A2 receptor (TBXA2R) were identified as critical signatures, and exhibited high expression in tumor-adjacent normal tissues. According to the ssGSEA results, ECM1, LIFR, SRPX and TBXA2R were all significantly associated with diverse immune cells, such as monocytes and neutrophils. Moreover, immunostaining of human HCC samples showed that these critical signatures all colocalized with CD14-positive monocytes. Our findings report the potential signatures of immune cells in HCC and confirm that they localize in monocytes of tumor-adjacent normal tissues. ECM1, LIFR, SRPX and TBXA2R could become new potential targets for predictive diagnosis, early intervention and immunotherapy of HCC in the future.

Functional Nanosheet Immunoswitches Reprogramming Innate Macrophages for Immunotherapy of Colorectal Cancer and Sepsis.

Macrophages are involved in the immunopathogenesis of cancer and inflammatory diseases and are a primary target for immunotherapy to reprogram the M1 and M2 phenotypes in tumor and inflammatory microenvironments. Herein, functional nanosheet immunoswitches that can bidirectionally polarize macrophages in tumor and inflammatory microenvironments are designed for effective immunotherapy of colorectal cancer and sepsis. WSe2 nanosheets are functionalized with palmitic acid to obtain an M1 immunoswitch (PA-WSe2) that promotes the polarization of macrophages toward the M1 phenotype in the tumor microenvironment by activating the STAT1 signaling pathway. WS2 nanosheets bearing linoleic acid are synthesized as an M2 immunoswitch (LA-WS2) that effectively polarizes macrophages to the M2 phenotype in the septic microenvironment by activating the STAT3 signaling pathway. The PA-WSe2 M1 immunoswitch upregulates the secretion of pro-inflammatory cytokines and reactive oxygen and nitrogen species (ROS and RNS) via M1 polarization, leading to the effective immunotherapy for colorectal cancer in vivo. In contrast, the LA-WS2 M2 immunoswitch induces the elevated production of anti-inflammatory cytokines and scavenging of ROS and RNS through M2 polarization, resulting in superior immunotherapy for severe sepsis in mice. These nanosheet immunoswitches can provide a route to immunotherapy for various cancers and inflammatory diseases.

Development of Novel Peptide-Based Radiotracers for Detecting FGL1 Expression in Tumors.

A novel immune checkpoint, FGL1, is a potentially viable target for tumor immunotherapy. The development of FGL1-targeted PET probes could provide significant insights into the immune system's status and the evaluation of treatment efficacy. A ClusPro 2.0 server was used to analyze the interaction between FGL1 and LAG3, and the candidate peptides were identified by using the Rosetta peptide derivate protocol. Three candidate peptides targeting FGL1, named FGLP21, FGLP22, and FGLP23, with a simulated affinity of -9.56, -8.55, and -8.71 kcal/mol, respectively, were identified. The peptides were readily conjugated with p-NCS-benzyl-NODA-GA, and the resulting compounds were successfully labeled with 68Ga in approximately 70% yields and radiochemical purity greater than 95%. In vitro competitive cell-binding assay demonstrated that all probes bound to FGL1 with IC50 ranging from 100 nM to 160 nM. Among the probes, PET imaging revealed that 68Ga-NODA-FGLP21 exhibited the best tumor imaging performance in mice bearing FGL1 positive Huh7 tumor. At 60 min p.i., the tumor uptake of 68Ga-NODA-FGLP21 was significantly higher than those of 68Ga-NODA-FGLP22 and 68Ga-NODA-FGLP23, respectively (2.51 ± 0.11% ID/g vs 1.00 ± 0.16% ID/g and 1.49 ± 0.05% ID/g). Simultaneously, the tumor-to-muscle uptake ratios of the former were also higher than those of the latter, respectively (19.40 ± 2.30 vs 9.65 ± 0.62 and 12.45 ± 0.72). In the presence of unlabeled FGLP21, the uptake of 68Ga-NODA-FGLP21 in Huh7 xenograft decreased to 0.81 ± 0.09% ID/g at 60 min p.i., which is similar to that observed in the FGL1 negative U87 MG tumor (0.46 ± 0.03% ID/g). The results were consistent with the immunohistochemical analysis and ex vivo autoradiography. No significant radioactivity was accumulated in normal organs, except for kidneys. In summary, a preclinical study confirmed that the tracer 68Ga-NODA-FGLP21 has the potential to specifically detect FGL1 expression in tumors with good contrast to the background.

Identification of TUBB3 as an immunotherapy target in lung cancer by genome wide in vivo CRISPR screening.

Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an in vivo genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both in vitro and in vivo assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients' survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer.

IL-8 contributes to functional diversity of tumor-infiltrating neutrophils: A new target for cancer immunotherapy.

In this issue of Developmental Cell, Tang etal. identify CD74high neutrophils as a subpopulation promoted by IL-8 in the tumor microenvironment of non-small lung cancer (NSCLC). These CD74high neutrophils support anti-tumor Tcell responses and enhance the efficacy of anti-PD-1 immunotherapy and targeted therapy in NSCLC.

CD155 promotes the progression of colorectal cancer by restraining CD8+ T cells via the PI3K/AKT/NF-κB pathway.

CD155 is a crucial factor in the regulation of T cell function and contributes to immune escape. CD155 upregulation has been found in several types of cancer. However, the mechanism by which CD155 regulates CD8+ T cell function in colorectal cancer remains unclear. Here we investigated the role and mechanism of CD155 in the regulation of CD8+ T cell function. We studied the expression of CD155 in colorectal cancer tissues through western blot, immunohistochemistry, and the TCGA database. We verified the effects of CD155 on the functions of colorectal cancer cells and CD8+ T cells through in vitro experiments. We demonstrated that CD155 affects CD8+ T cell migration and thus promotes tumor growth in a mouse subcutaneous tumor model. We then tested the changes in the PI3K/AKT/NF-κB pathway in CD8+ T cells by flow cytometry. We demonstrated that stable CD155 expression was negatively correlated with prognosis in colorectal cancer patients. In vitro experiments confirmed that CD155 does not affect tumor cell proliferation, migration, or invasion. We also revealed that CD155 downregulated the function and migration of CD8+ T cells in vivo and in vitro. Furthermore, CD155 might regulate CD8+ T cells function via the PI3K/AKT/NF-κB pathway. This study revealed that CD155 can promote the progression of colorectal cancer by regulating the PI3K / AKT-NF-κB pathway to promote the depletion of CD8+ T cells and reduce their migration to the tumor microenvironment. CD155 may become an important prognostic biomarker and an effective target for colorectal cancer immunotherapy.

Identification and validation VAT1 in gastric cancer through bioinformatics and experimental analysis.

This study investigated the expression pattern of Vesicular Amine Transporter 1 (VAT1) in gastric cancer (GC) and its impact on prognosis, alongside evaluating its potential as a biomarker for immunotherapy and chemotherapy. Analysis of transcriptomic data, supported by experimental validation, revealed that VAT1 is highly expressed in GC and is associated with poor prognosis. Kaplan-Meier and ROC analyses demonstrated VAT1's potential in GC diagnosis, while multivariate analysis confirmed its role as an independent risk factor. Gene set enrichment analysis indicated that VAT1 plays a role in regulating the MAPK signaling pathway and epithelial-mesenchymal transition (EMT) in GC. Immune infiltration analysis showed a positive correlation between VAT1 and immune cells, particularly macrophages, and a negative correlation with chemotherapy sensitivity. In vitro and in vivo experiments further confirmed VAT1's critical role in promoting GC cell proliferation and inhibiting apoptosis. Overall, VAT1 holds significant value not only in GC diagnosis and prognosis but also as a potential target for immunotherapy and overcoming drug resistance.

HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.

Practical management of adverse events in patients receiving tarlatamab, a delta-like ligand 3-targeted bispecific T-cell engager immunotherapy, for previously treated small cell lung cancer.

Tarlatamab is a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 (DLL3) and the cluster of differentiation 3 (CD3) molecule. In the phase 2 DeLLphi-301 trial of tarlatamab for patients with previously treated small cell lung cancer, tarlatamab 10 mg every 2 weeks achieved durable responses and encouraging survival outcomes. Analyses of updated safety data from the DeLLphi-301 trial demonstrated that the most common treatment-emergent adverse events were cytokine release syndrome (53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), and an emia (30%). Cytokine release syndrome was mostly grade 1 or 2 in severity, occurred primarily after the first or second tarlatamab dose, and was managed with supportive care, which included the administration of antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoids. Other treatment-emergent adverse effects of interest included neutropenia (16%) and immune effector cell-associated neurotoxicity syndrome and associated neurologic events (10%). Given that tarlatamab is the first T-cell engager approved for the treatment of small cell lung cancer, raising awareness with regard to the monitoring and management of tarlatamab-associated adverse events is essential. Here, the authors describe the timing, occurrence, and duration of these adverse events and review the management and risk-mitigation strategies used by clinical investigators during the DeLLphi-301 trial.

ATAD2 is a potential immunotherapy target for patients with small cell lung cancer harboring HLA-A∗0201.

Small cell lung cancer (SCLC) represents a highly aggressive neuroendocrine tumour with a dismal prognosis. Currently, the identification of a specific tumour antigen that can facilitate immune-based therapies for SCLC remains elusive. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyse cancer/testis antigens (CTAs) in SCLC cell lines and human tumour specimens. Immunohistochemistry of clinical specimens was performed to compare protein expression in SCLC, non-small cell lung cancer (NSCLC), and matched normal-adjacent tissues. Additionally, publicly available RNA sequencing databases were interrogated to identify gene expression patterns in different SCLC subtypes and in different disease stages. Distinct numbers and types of CTAs were identified across SCLC subtypes, with significantly higher expression levels of ATPase family AAA domain-containing protein 2 (ATAD2) observed in SCLC compared to normal adjacent tissues and NSCLC tissues. A dynamic expression pattern of ATAD2 was found throughout the clinical course of SCLC and exhibited a positive correlation with achaete-scute family bHLH transcription factor 1 (ASCL1) expression in SCLC. Immunopeptidomics analysis identified the YSDDDVPSV sequence derived from the HLA-A∗02:01 restriction epitope of ATAD2 as a highly promising tumour antigen candidate for potential immunotherapy applications. YSDDDVPSV immunopeptides were confirmed to be present in SCLC-A and SCLC-N with HLA-A∗02:01 restriction. Notably, HLA-A∗02:01T cells exhibited a robust response upon stimulation with YSDDDVPSV immunopeptide pulsed by T2 cells. Our findings highlight the potential of targeting the ATAD2 YSDDDVPSV immunopeptide for SCLC immunotherapy, thereby offering a promising avenue for the development of adoptive T cell therapies to effectively treat ASCL1-positive or NEUROD1-positive SCLC carrying HLA-A∗02:01. This study was supported by the National key R&D program of China (2022YFC2505000); National Natural Science Foundation of China (NSFC) general program (82272796) NSFC special program (82241229); CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-1-009); CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035); Aiyou foundation (KY201701). National key R&D program of China (2022YFC2505004). NSFC general program (81972905). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022012).

Immunotherapeutic strategies beyond the PD-1/PD-L1 pathway in head and neck squamous cell carcinoma - A scoping review on current developments in agents targeting TIM-3, TIGIT, LAG-3, and VISTA.

Head and neck squamous cell carcinoma (HNSCC) poses a considerable challenge due to its high incidence and mortality rates. Immunotherapy targeting PD-(L)1 emerges as a promising approach for HNSCC, as it has the potential to trigger a broad and long-lasting anti-tumor response. Nevertheless, the effectiveness of immunotherapy encounters hurdles, and only a small proportion of patients benefit, with many eventually experiencing relapse. Consequently, there is a pursuit of strategies to enhance overall treatment outcomes. Understanding the mechanisms driving resistance to PD-(L)1 inhibition and devising strategies to overcome these challenges are vital for advancing more effective treatments. Furthermore, gaining insights into the mechanisms of action and safety profiles of novel combination therapies is critical for their successful adoption in clinical practice. As a result, current research is dedicated to investigating various immunotherapeutic agents beyond the PD-1/PD-L1 axis. This review offers a comprehensive overview of the existing immunotherapy strategies in HNSCC with a focus on TIM-3, TIGIT, LAG-3, and VISTA. The aim is to lay a strong foundation for the continual advancement of therapies for HNSCC.

PD-L1-CD80 interactions are required for intracellular signaling necessary for dendritic cell migration.

Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) interactions are targets for immunotherapies aimed to reinvigorate T cell function. Recently, it was documented that PD-L1 regulates dendritic cell (DC) migration through intracellular signaling events. In this study, we find that both preclinical murine and clinically available human PD-L1 antibodies limit DC migration. We show that cis interactions between PD-L1 and CD80 are critical for promoting migration and define specific regions within these proteins necessary for migration. Furthermore, we demonstrate that αPD-L1 significantly impedes DC migration in a B16 melanoma tumor model. Last, we outline how blocking cis PD-L1:CD80 interactions or mutation of the intracellular domain of PD-L1, in an imiquimod-induced murine model of psoriasis, limits DC migration to the lymph node, decreases interleukin-17 production by CD4+ T cells in the lymph node, and reduces epidermal thickening. Therefore, PD-L1 and CD80 interactions are important regulators of DC migration to the draining lymph node.

Identification of TTLL8, POTEE, and PKMYT1 as immunogenic cancer-associated antigens and potential immunotherapy targets in ovarian cancer

ABSTRACT Most high-grade serous ovarian cancers (OC) do not respond to current immunotherapies. To identify potential new actionable tumor antigens in OC, we performed immunopeptidomics on a human OC cell line expressing the HLA-A02:01 haplotype, which is commonly expressed across many racial and ethnic groups. From this dataset, we identified TTLL8, POTEE, and PKMYT1 peptides as candidate tumor antigens with low expression in normal tissues and upregulated expression in OC. Using tissue microarrays, we assessed the protein expression of TTLL8 and POTEE and their association with patient outcomes in a large cohort of OC patients. TTLL8 was found to be expressed in 56.7% of OC and was associated with a worse overall prognosis. POTEE was expressed in 97.2% of OC patients and had no significant association with survival. In patient TILs, increases in cytokine production and tetramer-positive populations identified antigen-specific CD8 T cell responses, which were dependent on antigen presentation by HLA class I. Antigen-specific T cells triggered cancer cell killing of antigen-pulsed OC cells. These findings suggest that TTLL8, POTEE, and PKMYT1 are potential targets for the development of antigen-targeted immunotherapy in OC.

Tertiary lymphoid structures are associated with enhanced macrophage activation and immune checkpoint expression, and predict outcome in cervical cancer.

Cervical tumors are usually treated using surgery, chemotherapy, and radiotherapy, and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in cancer patients. We evaluated the cervical tumor immune microenvironment, specifically focusing on TLS, using combined high-throughput phenotyping, soluble factor concentration dosage in the TME and spatial interaction analyses. We found that TLS presence was associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DCs). Furthermore, this myeloid cell activation was associated with expression of immune checkpoints, such as PD-L1 and CD40, and proximity of activated conventional type 2 DCs (DC2) to CD8+ T cells, indicating better immune interactions and tumor control. Finally, we associated TLS presence, greater B cell density, and activated DC density with improved progression-free survival, substantiating TLS presence as a potential prognostic marker. Our results provide evidence that TLS presence denotes cell activation and immunotherapy target expression.

CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex

Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2-RACK1-HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.

A Systematic Review and Meta-analysis on the Safety and Efficacy of CAR T Cell Therapy Targeting GPRC5D in Patients with Multiple Myeloma: A New Insight in Cancer Immunotherapy.

Despite ongoing advances and introducing innovative therapeutic approaches for the treatment of multiple myeloma (MM), relapses are common, with low overall survival rates. G protein-coupled receptor, class C, group 5, and member D (GPRC5D) has been expressed in several myeloma cell lines and has demonstrated encouraging outcomes results in in-vitro studies as a potential target for immunotherapies. We aimed to investigate the safety and efficacy of GPRC5D-targeted CAR T cell therapies in MM patients. On August 24, 2023, the databases of PubMed, Scopus, Embase, and Web of Science were systematically searched for pertinent studies. After completing a two-step title/abstract and full-text screening process, the eligible studies were included. Following the screening of 107 articles, four studies of 130 multiple myeloma patients treated with GPRC5D-targeted CAR T-cell therapy were included. The meta-analyses showed an ORR of 87% (95% CI [81- 93%]), with 74% (95% CI [65-73%]) for those with prior BCMA-targeted therapy and 88% (95% CI [78-99%]) for those without. PR was 25%, VGPR 33%, and CR/sCR 48%, with 65% achieving MRD-negativity. In terms of safety, hematologic AEs were common, with anemia reported in 86% of patients. Non-hematologic common AEs included CRS (83%, 5% grade ≥3) and hypocalcemia (63%, 10% grade ≥3). No significant publication bias was detected. GPRC5D is an active and safe target that shows promising results in the treatment of relapsed and/or refractory (R/R) MM and heavily pretreated patients.

Recent advances in immunotherapy targeting amyloid-beta and tauopathies in Alzheimer's disease.

Alzheimer's disease, a devastating neurodegenerative disorder, is characterized by progressive cognitive decline, primarily due to amyloid-beta protein deposition and tau protein phosphorylation. Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer's disease. Conventional drugs, such as donepezil, can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline. Currently, active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer's disease and other transgenic animal models, attracting considerable attention. However, the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab. This review first discusses the advancements in the pathogenesis of Alzheimer's disease and active and passive immunotherapies targeting amyloid-beta and tau proteins. Furthermore, it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects. Although some antibodies have shown promise in patients with mild Alzheimer's disease, substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer's disease.

A pan-cancer analysis: predictive role of ZNF32 in cancer prognosis and immunotherapy response

The zinc finger protein 32 (ZNF32) has been associated with high expression in various cancers, underscoring its significant function in both cancer biology and immune response. To further elucidate the biological role of ZNF32 and identify potential immunotherapy targets in cancer, we conducted an in-depth analysis of ZNF32. We comprehensively investigated the expression of ZNF32 across tumors using diverse databases, including TCGA, CCLE, TIMER2.0, KM-Plotter, cBioPortal, ImmuCellAI. We investigated correlations between ZNF32 expression and various factors such as prognosis, immune infiltration, immunotherapy, DNA methylation, and biological functions. Furthermore, we performed in vitro research to validate the significance of ZNF32 in head and neck cancer (HNSC). Our study revealed that ZNF32 was high in various types of cancer, including ACC, BRCA, and others, indicating its important potential as a prognostic biomarker. Significant changes in CNA and DNA methylation were associated with high ZNF32 expression. ZNF32 was notably linked to various immune characteristics, including immune cell infiltration, MSI, TMB and immune checkpoint gene expression, indicating its potential in informing immunotherapy approaches. Interestingly, in FaDu and CAL27 cell lines, the group with elevated ZNF32 expression exhibited increased levels of immune checkpoint markers, such as CTLA-4 and PD-L1. Overexpression of ZNF32 significantly enhanced proliferation and migration in FaDu and CAL27 cell lines, as demonstrated through CCK-8 assays, colony formation, flow cytometry, Transwell migration, and Boyden invasion assays. Our in vitro experiments confirmed that ZNF32 promotes malignant behavior by driving HNSC cell proliferation and migration. These results imply that ZNF32 might be a promising target for tumor prognosis and immunotherapy. Our results highlight the important role of ZNF32 in tumorigenesis and provide novel perspectives for potential cancer treatment strategies.