Accumulating evidence has shown that different immunotherapies for ovarian cancer might overcome barriers to resistance to standard chemotherapy. The vaccine immunotherapy may be a useful one addition to conditional chemotherapy regimens. The present study investigated the use of vaccine of ovarian cancer stem cells (CSCs) to inhibit ovarian cancer growth.

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.

To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies.

Although various immunotherapies have exerted promising effects on cancer treatment, many patients with cancer continue to exhibit poor responses. Because of its negative regulatory effects on T cells and its biological functions related to immune and inflammatory responses, there has been considerable emphasis on a protein-coding gene named lymphocyte-activation gene 3 (LAG3). Recently, evidence demonstrated marked synergy in its targeted therapy with programmed death-1 and programmed death-1 ligand-1 (PD-1/PD-L1) blockade, and a variety of LAG3 targeted agents are in clinical trials, indicating the important role of LAG3 in immunotherapy. This mini-review discusses preclinical and clinical studies investigating PD-1 pathway blockade in combination with LAG3 inhibition as a potentially more effective immunotherapy strategy for further development in the clinic. This strategy might provide a new approach for the design of more effective and precise cancer immune checkpoint therapies.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells' infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment.

To determine whether antibiotic treatment is a risk factor for immune-related adverse events (irAEs) across different patients with cancer receiving anti-PD-1/PD-L1 therapies.

Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built a neural network incorporating factors associated with neoantigen production, presentation, and recognition, which exhibited potential for differentiating cancer patients likely to benefit from ICIs. Our findings highlight the clinical utility of evaluating HLA-I tumor antigen presentation capacity and describe how ICI response may depend on HLA-mediated immunity.

Low tumor mutational burden and absence of T cells within the tumor sites are typical characteristics of "cold immune tumors" that paralyzes the immune system. The strategy of reversing "cold tumors" to "hot tumors" infiltrated high degree of T cells in order to activate anti-tumor immunity has attracted lots of attentions. Herein, immunogenic core-shell Au@Se NPs is fabricated by gold-selenium coordination bond to realize nanoparticles-mediated local photothermal-triggered immunotherapy. As expected, incorporation of gold nanostars (AuNSs) with improved photothermal stability and conversion efficiency promotes the disintegration and transformation of selenium nanoparticles (SeNPs), thus leading to enhanced cancer cells apoptosis by producing higher hyperthermia. Moreover, the results of in vivo experiments demonstrate that the synergy between SeNPs-mediated chemotherapy and AuNSs-induced photothermal therapy not only generated a localized antitumor-immune response with excellent cancer killing effect under the presence of tumor-associated antigens, but also effectively reprogrammed the tumor associated macrophages (TAMs) from M2 to M1 phenotype with tumoricidal activity to devour distant tumors. Without a doubt, this study not only provides a potent strategy to reverse the immunosuppressive tumor microenvironment, but also offers a new insight for potential clinical application in tumor immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. Immunotherapy has achieved success in the treatment of multiple malignancies. However, the efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. In this research, we aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy.

As a regulatory subunit of cyclin kinase, CKS1B promotes cancer development and is associated with poor prognosis in multiple cancer patients. However, the intrinsic role of CKS1B in pancreatic cancer remains elusive. In our research, CKS1B expression in pancreatic tumor tissue was higher than that in normal tissue by TCGA, Oncomine and CPTAC databases analysis. Similar result was verified in our center tissues by qRT-PCR. CKS1B expression was closely relevant to histologic grading, prognosis, and TMB. GSEA showed that CKS1B mainly participated in the regulation of autophagy and T cell receptor signaling pathway. Furthermore, CIBERSORT analysis showed that there was a strong correlation between CKS1B expression and tumor immune cells infiltration. Drug sensitivity analysis showed that patients with high CKS1B expression appeared to be more sensitive to gemcitabine, 5-fluorouracil, and paclitaxel. We then investigated cell viability and migratory ability by CCK8 and transwell assay, respectively. Results indicated that CKS1B knockdown by short hairpin RNA significantly reduced pancreatic cancer cell viability and invasion via regulating PD-L1 expression. In conclusion, our research further demonstrates the role of CKS1B in pancreatic cancer and the signaling pathways involved. The association of CKS1B with immune infiltration and immune checkpoint may provide a new direction for immunotherapy of pancreatic cancer.

The tumor immune microenvironment can influence the prognosis and treatment response to immunotherapy. We aimed to develop a non-invasive radiomic signature in high-grade glioma (HGG) to predict the absolute density of tumor-associated macrophages (TAMs), the preponderant immune cells in the microenvironment of HGG. We also aimed to evaluate the association between the signature, and tumor immune phenotype as well as response to immunotherapy.

Breast cancer (BC) is one of the major dangerous tumors threatening women's lives. We here aimed to sort out prognostic immune-related genes by univariate Cox regression analysis and build a model of immune-related genes for forecasting the prognosis of BC patients. We identified UL16 binding protein 2 (ULBP2) as a valuable gene for study in the model using related databases and algorithms analysis. We found the stromal and immune cells scores were higher in ULBP2 high expression group and ULBP2 was related to kinds of immune cells, most importantly had negative correlation with CD8+ T cell. Notably, ULBP2 was positively correlated with tumor mutational burden (TMB) and had relationship with many immune checkpoints. Correlation analysis revealed that ULBP2 expression was closely linked to the clinicopathological characters and negatively related to BC patient survival. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed the functional enrichment of differential genes related to ULBP2. Gene Set Enrichment Analysis (GSEA) indicated pathway enrichment in ULBP2 high and low expression groups. In short, this study comprehensively investigated the potential function of ULBP2 in BC, which might make ULBP2 to be an important therapeutic target for BC.

Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten-/- ). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.

We performed a single-arm exploratory clinical trial that is ongoing and registered at ClinicalTrials.gov (NCT03093688). Patients were infused with autologous iNKT cells, PD-1 + CD8+ T cells, and dendritic cells every 3-5 weeks, which was considered 1 cycle. The primary endpoints were safety and objective tumor response. The preliminary results from the first three patients are reported here. The first patient received 16 cycles. Computed tomography (CT) examination revealed a stable disease (SD) response after 4 cycles and progressive disease (PD) response after 11 cycles. For the second patient that received 10 cycles, CT examination revealed an SD response after 4 cycles and a PD response after 9 cycles. For the third patient who was treated with 6 cycles, CT examination revealed an SD response after 4 cycles. The patients suffered from only grade 1-2 adverse events. iNKT cell and PD-1 + CD8+ T cell-based immunotherapy showed a manageable tolerability profile.

Abnormal N6-methyladenosine (m6A) modification levels caused by METTL3 have been identified to be a critical regulator in human cancers, and its roles in the immune microenvironment and the relationship between targeted therapy and immunotherapy sensitivity in gastric cancer (GC) remain poorly understood. In this study, we assessed the transcriptome-wide m6A methylation profile after METTL3 overexpression by m6A sequencing and RNA sequencing in BGC-823 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the function of core targets of METTL3. Eighteen methylation core molecules were identified in GC patients by combining transcriptome and methylome sequencing. GC patients can be separated into two subtypes based on the expression of 18 methylation core molecules. Furthermore, subgroup analysis showed that patients with different subtypes had a different OS, PFS, stage, grade, and TMB. Gene set enrichment analysis (GSEA) showed that immune-related pathways were enriched among subtype A. The ESTIMATE analysis suggested that the extent of infiltration of immune cells was different in two subtypes of GC patients. Tumor Immune Dysfunction and Exclusion (TIDE) and The Cancer Immunome Atlas (TCIA) database also showed that there were significant differences in the efficacy of immunotherapy among different types of GC patients. Altogether, our results reveal that METTL3-mediated m6A methylation modification is associated with the immune microenvironment and the effects of immunotherapy in GC patients. Our findings provide novel insights for clinicians in the diagnosis and optimal treatment of GC patients.

Immunotherapy for malignant tumors has made great progress, but many patients do not benefit from it. The complex intratumoral heterogeneity (ITH) hindered the in-depth exploration of immunotherapy. Conventional bulk sequencing has masked intratumor complexity, preventing a more detailed discovery of the impact of ITH on treatment efficacy. Hence, we initiated this study to explore ITH at the multi-omics spatial level and to seek prognostic biomarkers of immunotherapy efficacy considering the presence of ITH.

A KD-control human induced pluripotent stem cells (iPSCs) line (PUMCi002-A) was generated from dermal fibroblasts of a Krabbe patient's father with a c.461C>A mutation in Galactocerebrosidase (GALC) gene. The pluripotency, in vitro differentiation potential and karyotype stability of generated iPSC line were analyzed and confirmed. This cell line can be exploited as a control iPSC line to better understand the mechanisms involved in GALC-associated Krabbe disease and provide plausible new therapeutic directions.

Globoid cell leukodystrophy (GLD) is a devastating neurodegenerative disease characterized by widespread demyelination caused by galactocerebrosidase defects. Changes in GLD pathogenesis occurring at the molecular level have been poorly studied in human-derived neural cells. Patient-derived induced pluripotent stem cells (iPSCs) are a novel disease model for studying disease mechanisms and allow the generation of patient-derived neuronal cells in a dish.

Co-stimulation regulates T cell activation, but it remains unclear whether co-stimulatory pathways also control T cell differentiation. We used mass cytometry to profile T cells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral T cells can acquire. CTLA-4 imposes major boundaries on CD4+ T cell phenotypes, whereas PD-1 subtly limits CD8+ T cell phenotypes. By computationally reconstructing T cell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in T cell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of T cell phenotypes.