IFN-α/ß/IFN-γ/IL-15 pathways identify GBP1-expressing tumors with an immune-responsive phenotype.

Immunotherapy is widely used in cancer treatment; however, only a subset of patients responds well to it. Significant efforts have been made to identify patients who will benefit from immunotherapy. Successful anti-tumor immunity depends on an intact cancer-immunity cycle, especially long-lasting CD8+ T-cell responses. Interferon (IFN)-α/ß/IFN-γ/interleukin (IL)-15 pathways have been reported to be involved in the development of CD8+ T cells. And these pathways may predict responses to immunotherapy. Herein, we aimed to analyze multiple public databases to investigate whether IFN-α/ß/IFN-γ/IL-15 pathways could be used to predict the response to immunotherapy. Results showed that IFN-α/ß/IFN-γ/IL-15 pathways could efficiently predict immunotherapy response, and guanylate-binding protein 1 (GBP1) could represent the IFN-α/ß/IFN-γ/IL-15 pathways. In public and private cohorts, we further demonstrated that GBP1 could efficiently predict the response to immunotherapy. Functionally, GBP1 was mainly expressed in macrophages and strongly correlated with chemokines involved in T-cell migration. Therefore, our study comprehensively investigated the potential role of GBP1 in immunotherapy, which could serve as a novel biomarker for immunotherapy and a target for drug development.

NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice.

BACKGROUND: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance. METHODS: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice. RESULTS: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance. CONCLUSION: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.

Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review.

Background and Objective: Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods: For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings: Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions: Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

Impact of lymphadenectomy extent on immunotherapy efficacy in postresectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study.

BACKGROUND: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel 'immunotherapy-driven' LN dissection strategy. MATERIALS AND METHODS: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. RESULTS: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7-13); 66 had a DLN count greater than 16 (median, IQR: 23, 19-29). With a median follow-up time of 14.3 months (95% CI: 11.0-17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1-11.7) months, 11.7 (95% CI: 7.9-15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1-6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07-0.89), P =0.03]; [validation cohort: HR=0.46 (95% CI: 0.22-0.96), P =0.04]; [entire cohort: HR=0.53 (95% CI: 0.32-0.89), P =0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065-0.845, P =0.027). CONCLUSIONS: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.

Heterogeneity of the tumor immune microenvironment and clinical interventions.

The tumor immune microenvironment (TIME) is broadly composed of various immune cells, and its heterogeneity is characterized by both immune cells and stromal cells. During the course of tumor formation and progression and anti-tumor treatment, the composition of the TIME becomes heterogeneous. Such immunological heterogeneity is not only present between populations but also exists on temporal and spatial scales. Owing to the existence of TIME, clinical outcomes can differ when a similar treatment strategy is provided to patients. Therefore, a comprehensive assessment of TIME heterogeneity is essential for developing precise and effective therapies. Facilitated by advanced technologies, it is possible to understand the complexity and diversity of the TIME and its influence on therapy responses. In this review, we discuss the potential reasons for TIME heterogeneity and the current approaches used to explore it. We also summarize clinical intervention strategies based on associated mechanisms or targets to control immunological heterogeneity.

Molecular Insights into the Binding Behavior of Imidazolium Ionic Liquids to the Receptor Binding Domain of the SARS-CoV-2 Spike Protein.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is considered as a key target for the design and development of COVID-19 drugs and inhibitors. Due to their unique structure and properties, ionic liquids (ILs) have many special interactions with proteins, showing great potential in biomedicine. Nevertheless, few research studies have been carried out on ILs and the spike RBD protein. Here, we explore the interaction of ILs and the RBD protein through large-scale molecular dynamics simulations (4 µs in total). It was found that IL cations with long alkyl chain lengths (nchain) could spontaneously bind to the cavity region of the RBD protein. The longer the alkyl chain is, the stabler the cations bind to the protein. The binding free energy (ΔG) had the same trend, peaking at nchain = 12 with -101.19 kJ/mol. The cationic chain lengths and their fit to the pocket are decisive factors that influence the binding strength of cations and proteins. The cationic imidazole ring has a high contact frequency with phenylalanine and tryptophan, and the hydrophobic residues phenylalanine, valine, leucine, and isoleucine are the most interacting residues with side chains of cations. Meanwhile, through analysis of the interaction energy, the hydrophobic and π-π interactions are the main contributors to the high affinity between cations and the RBD protein. In addition, the long-chain ILs would also act on the protein through clustering. These studies not only provide insights into the molecular interaction between ILs and the RBD of SARS-CoV-2 but also contribute to the rational design of IL-based drugs, drug carriers, and selective inhibitors as a therapeutic for SARS-CoV-2.

Synergistic immunotherapy targeting cancer-associated anemia: prospects of a combination strategy.

Cancer-associated anemia promotes tumor progression, leads to poor quality of life in patients with cancer, and even obstructs the efficacy of immune checkpoint inhibitors therapy. However, the precise mechanism for cancer-associated anemia remains unknown and the feasible strategy to target cancer-associated anemia synergizing immunotherapy needs to be clarified. Here, we review the possible mechanisms of cancer-induced anemia regarding decreased erythropoiesis and increased erythrocyte destruction, and cancer treatment-induced anemia. Moreover, we summarize the current paradigm for cancer-associated anemia treatment. Finally, we propose some prospective paradigms to slow down cancer-associated anemia and synergistic the efficacy of immunotherapy. Video Abstract.

Chromothripsis is correlated with reduced cytotoxic immune infiltration and diminished responsiveness to checkpoint blockade immunotherapy.

Background: Chromothripsis caused massive, clustered genomic rearrangements is prevalent in cancer and is considered a new paradigm for tumorigenesis and progression. In this study, we investigated the association among chromothripsis, anti-tumor immune responses, and responsiveness to immune checkpoint blockade (ICB). Methods: Quantification of immune cell infiltration and functional enrichment of immune-related signaling pathways were performed in the discovery set (n = 9403) and the validation set (n = 1140). we investigated the association between chromothripsis and anti-tumor immune responses. In the immunotherapy cohort, copy number alteration-based chromothripsis scores (CPSs) were introduced to assess the extent of chromothripsis to evaluate its association with responsiveness to ICB. Results: In the discovery set and the validation set, the ratios of CD8+ T cells to Tregs, TAMs, and MDSCs were significantly lower in tumors with chromothripsis (P = 1.5 × 10-13, P = 5.4 × 10-8, and P = 1.2 × 10-4, respectively, TCGA; P = 1.0 × 10-13, P = 3.6 × 10-15, and P = 3.3 × 10-3, respectively, PCAWG). The relevant pathways underlying the antitumor immune effect were significantly enriched in tumors without chromothripsis. Chromothripsis can be used as an independent predictor, and patients with low-CPSs experienced longer overall survival (OS) after immunotherapy [HR, 1.90; 95% confidence interval, 1.10-3.28; P = 0.019]. Conclusions: Our findings highlight the reduced cytotoxic immune infiltration in tumors with chromothripsis and enhanced immunosuppression in the tumor microenvironment. Chromothripsis can thus be used as a potential indicator to help identify patients who will respond to ICB, which could complement established biomarkers.

Caspase-8 contributes to an immuno-hot microenvironment by promoting phagocytosis via an ecto-calreticulin-dependent mechanism.

BACKGROUND: Caspase-8 (Casp8) acts as an initiator in cell apoptosis signaling. However, the role of Casp8 in tuning the tumor immune microenvironment remains controversial due to the complicated crosstalk between immune-tolerogenic apoptotic cell death and immunogenic cell death cascades. METHODS: The Cancer Genome Atlas (TCGA) and publicly accessible immune checkpoint blockade (ICB)-treated cohorts were used to investigate the clinical relevance of Casp8. A tumor-bearing mouse model was used to characterize changes in the tumor microenvironment and to explore the efficacy of ICB treatment under Casp8 knockout conditions. RESULTS: By exploring TCGA datasets, we showed that the expression level of Casp8 was associated with an immuno-hot microenvironment across various solid tumor types. Casp8 deficiency leads to decreased CD8+ T cell infiltration and resistance to anti-PD-L1 therapy in a mouse model. Mechanistically, Casp8 deficiency or pharmacological disruption results in impaired ecto-calreticulin transition in tumor cells, which in turn hampers antigen presentation in draining lymph nodes. Furthermore, radiotherapy restored sensitivity to anti-PD-L1 treatment via elevated calreticulin surface expression. CONCLUSIONS: Our data revealed a causative role of Casp8 in modulating the immunogenicity of tumor cells and responsiveness to ICB immunotherapies and proposed radiotherapy as a salvage approach to overcome Casp8 deficiency-mediated ICB resistance.

Ring Repeating Unit: An Upgraded Structure Representation of Linear Condensation Polymers for Property Prediction.

Unique structure representation of polymers plays a crucial role in developing models for polymer property prediction and polymer design by data-centric approaches. Currently, monomer and repeating unit (RU) approximations are widely used to represent polymer structures for generating feature descriptors in the modeling of quantitative structure-property relationships (QSPR). However, such conventional structure representations may not uniquely approximate heterochain polymers due to the diversity of monomer combinations and the potential multi-RUs. In this study, the so-called ring repeating unit (RRU) method that can uniquely represent polymers with a broad range of structure diversity is proposed for the first time. As a proof of concept, an RRU-based QSPR model was developed to predict the associated glass transition temperature (Tg) of polyimides (PIs) with deterministic values. Comprehensive model validations including external, internal, and Y-random validations were performed. Also, an RU-based QSPR model developed based on the same large database of 1321 PIs provides nonunique prediction results, which further prove the necessity of RRU-based structure representation. Promising results obtained by the application of the RRU-based model confirm that the as-developed RRU method provides an effective representation that accurately captures the sequence of repeat units and thus realizes reliable polymer property prediction by data-driven approaches.

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Neoantigens in precision cancer immunotherapy: from identification to clinical applications.

ABSTRACT: Immunotherapies targeting cancer neoantigens are safe, effective, and precise. Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing; proteomic techniques such as mass spectrometry; and bioinformatics tools based on high-throughput sequencing data, mass spectrometry data, and biological databases. Neoantigen-related therapies are widely used in clinical practice and include neoantigen vaccines, neoantigen-specific CD8+ and CD4+ T cells, and neoantigen-pulsed dendritic cells. In addition, neoantigens can be used as biomarkers to assess immunotherapy response, resistance, and prognosis. Therapies based on neoantigens are an important and promising branch of cancer immunotherapy. Unremitting efforts are needed to unravel the comprehensive role of neoantigens in anti-tumor immunity and to extend their clinical application. This review aimed to summarize the progress in neoantigen research and to discuss its opportunities and challenges in precision cancer immunotherapy.

High-throughput single-сell sequencing in cancer research.

With advances in sequencing and instrument technology, bioinformatics analysis is being applied to batches of massive cells at single-cell resolution. High-throughput single-cell sequencing can be utilized for multi-omics characterization of tumor cells, stromal cells or infiltrated immune cells to evaluate tumor progression, responses to environmental perturbations, heterogeneous composition of the tumor microenvironment, and complex intercellular interactions between these factors. Particularly, single-cell sequencing of T cell receptors, alone or in combination with single-cell RNA sequencing, is useful in the fields of tumor immunology and immunotherapy. Clinical insights obtained from single-cell analysis are critically important for exploring the biomarkers of disease progression or antitumor treatment, as well as for guiding precise clinical decision-making for patients with malignant tumors. In this review, we summarize the clinical applications of single-cell sequencing in the fields of tumor cell evolution, tumor immunology, and tumor immunotherapy. Additionally, we analyze the tumor cell response to antitumor treatment, heterogeneity of the tumor microenvironment, and response or resistance to immune checkpoint immunotherapy. The limitations of single-cell analysis in cancer research are also discussed.

Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy.

Despite the unprecedented success of immune checkpoint inhibitors (ICIs) as anti-cancer therapy, it remains a prevailing clinical need to identify additional mechanisms underlying ICI therapeutic efficacy and potential drug resistance. Here, using lineage tracking in cancer patients and tumor-bearing mice, we demonstrate that erythroid progenitor cells lose their developmental potential and switch to the myeloid lineage. Single-cell transcriptome analyses reveal that, notwithstanding quantitative differences in erythroid gene expression, erythroid differentiated myeloid cells (EDMCs) are transcriptionally indistinguishable from their myeloid-originated counterparts. EDMCs possess multifaceted machinery to curtail T cell-mediated anti-tumor responses. Consequently, EDMC content within tumor tissues is negatively associated with T cell inflammation for the majority of solid cancers; moreover, EDMC enrichment, in accordance with anemia manifestation, is predictive of poor prognosis in various cohorts of patients undergoing ICI therapy. Together, our findings reveal a feedforward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression.

Heterogeneity of the tumor immune microenvironment and its clinical relevance.

During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies.

The roles of CC chemokines in response to radiation.

Radiotherapy is an effective regimen for cancer treatment alone or combined with chemotherapy or immunotherapy. The direct effect of radiotherapy involves radiation-induced DNA damage, and most studies have focused on this area to improve the efficacy of radiotherapy. Recently, the immunomodulatory effect of radiation on the tumour microenvironment has attracted much interest. Dying tumour cells can release multiple immune-related molecules, including tumour-associated antigens, chemokines, and inflammatory mediators. Then, immune cells are attracted to the irradiated site, exerting immunostimulatory or immunosuppressive effects. CC chemokines play pivotal roles in the trafficking process. The CC chemokine family includes 28 members that attract different immune subsets. Upon irradiation, tumour cells or immune cells can release different CC chemokines. Here, we mainly discuss the importance of CCL2, CCL3, CCL5, CCL8, CCL11, CCL20 and CCL22 in radiotherapy. In irradiated normal tissues, released chemokines induce epithelial to mesenchymal transition, thus promoting tissue injury. In the tumour microenvironment, released chemokines recruit cancer-associated cells, such as tumour-infiltrating lymphocytes, myeloid-derived suppressor cells and tumour-associated macrophages, to the tumour niche. Thus, CC chemokines have protumour and antitumour properties. Based on the complex roles of CC chemokines in the response to radiation, it would be promising to target specific chemokines to alleviate radiation-induced injury or promote tumour control.

Somatostatin Receptor 2: A Potential Predictive Biomarker for Immune Checkpoint Inhibitor Treatment.

Somatostatin receptor 2 (SSTR2), the most abundant receptor of somatostatin (SST), possesses immunoreactivity and is altered in many cancers. However, the association between SSTR2 and efficacy of immune checkpoint inhibitors (ICIs) has not yet been reported. Immunohistochemistry (IHC) information across 20 cancers was collected from the Human Protein Atlas (HPA) and used to analyze the expression of SSTR2. Immune signatures collected from public databases, such as BioCarta or Reactome, were used to investigate the association between SSTR2 and the tumor microenviroment in the Cancer Genome Atlas (TCGA). Data from cohorts treated with ICIs were collected to assess whether SSTR2 is associated with benefits from ICIs treatment. In the HPA, we found the SSTR2 IHC-positive rate of 13 cancers to be above 50%. Five types of cancer express SSTR2 mildly (positive rate: 25%-50%), while the remaining two types of cancer barely stained SSTR2-positive (positive rate: 0%-24%). In TCGA analysis, immune cell signatures and immune function pathways were enriched in high SSTR2 expression groups in most cancers. In each ICIs treated cohort, patients with high SSTR2 expression experienced numerically superior objective response rate (Braun: 14.8% vs 13.4%, p = 0.85; Gide: 69.4% vs 40.5%, p = 0.025; Mariathasan: 22.4% vs 16.7%, p = 0.233; Miao: 37.5% vs 11.8%; Riaz: 32.0% vs 7.7%, p = 0.067) and overall survival (Braun: HR (95%CI): 0.80 [0.62-1.04], p = 0.80; Gide: HR (95%CI): 0.61 [0.29-1.30], p = 0.20; Mariathasan: HR (95%CI): 0.83 [0.64-1.08], p = 0.16; Miao: HR (95%CI): 0.24 [0.086-0.65], p = 0.0028; Nathanson cohort: HR (95%CI): 0 [0-inf], p = 0.18; Riaz: HR (95%CI): 0.24 [0.086-0.65], p = 0.028) than patients with low SSTR2 expression. In pooled cohort, we found these differences were significant (Pool: 24.6% vs 16.7%, p = 0.0077; HR (95% CI): 0.77 [0.65-0.91], p = 0.0018). Our results suggest that SSTR2 is a potential predictive biomarker for response to ICIs.

ENPEP as a potential predictor of immune checkpoint inhibitor efficacy.

BACKGROUND: The gene ENPEP encodes glutamyl aminopeptidase, which can cut N-terminal aspartic acid from angiotensin II, and is related to tumorigenesis and immune microenvironment, however, the association between the expression of ENPEP and benefits of immune checkpoint inhibitors (ICIs) has had no investigation. METHODS: We assess the immunotherapeutic predictive performance of ENPEP expression and mutation in multiple cohorts, including one discovery cohort (Pender cohort), four validation cohorts (Hugo cohort; Liu cohort; Mariathasan cohort; Zhao cohort), and one mutation cohort (Miao cohort). Cohorts from The Cancer Genome Atlas (TCGA) were used to explore mechanism and analysis prognosis. RESULTS: In the discovery cohort, patients with lower ENPEP expression had superior response rates (47.2% vs. 36.1%) and over-all survival (OS) (HR [95% CI] = 0.61 [0.39-0.96]; p = 0.032) compared with those with higher ENPEP expression. The association between ENPEP and immunotherapy efficacy was consistently observed in validation cohorts (Hugo: OS HR [95% CI] = 0.41 [0.11-1.45], p = 0.158; Liu: OS HR [95% CI] = 0.73 [0.44-1.20], p = 0.211; Mariathasan: OS HR [95% CI] = 0.84 [0.65-1.09], p = 0.181; Zhao: OS HR [95% CI] = 0.20 [0.04-1.01], p = 0.033; Pooled cohort: OS HR [95% CI] = 0.76 [0.61-0.95], p = 0.015), and in the mutation cohort (ENPEP mutation vs. wild type (WT), OS HR [95% CI] = 0.46 [0.26-0.93], p = 0.017). Reliably, ENPEP is associated with M2 macrophage infiltration and activation in TCGA. CONCLUSIONS: Our results demonstrated ENPEP is a potential biomarker to classify patients' response to ICIs treatment.

A QSTR model for toxicity prediction of pesticides towards Daphnia magna.

Because of the large amount of pesticides discharged into rivers, adverse effects could be induced to aquatic organisms. Daphnia magna is often used as an indicator organism to evaluate the toxicity of pesticides. In this study, a quantitative structure-toxicity relationship (QSTR) model was established based on norm descriptors for predicting the acute toxicity of pesticides to Daphnia magna. The model results showed the good predictability (Rtraining2 = 0.8045, Rtesting2 = 0.8224). The validation results of internal validation, external validation, Y-randomization test and application domain analysis demonstrated the model's stability, reliability and robustness. Therefore, the above results indicate that norm descriptors might be universal for describing the relationship between the toxicity and structures of pesticides compounds. Moreover, some pesticides' toxicities without experimental data were also predicted by this model.

Programmed Cell Death Protein Ligand 2 Is a Potential Biomarker That Predicts the Efficacy of Immunotherapy.

Immune checkpoint inhibitor (ICI) responses vary, and biomarkers for predicting responders are urgently needed. Growing evidence points to the association between programmed cell death protein ligand 2 (PDL2) and ICI benefits, while clinical evidences were lacking. Thus, we consolidated five public ICI-treated cohorts to investigate the association between PDL2 expression and ICI treatment prognosis. Immune cell signatures and IFN-γ signatures are investigated in The Cancer Genome Atlas (TCGA) dataset and later in ICI-treated cohorts to explore the association between PDL2 and antitumor immunity in the tumor microenvironment (TME). We found that immune cell signatures and IFN-γ signatures were enriched in the PDL2-high group in TCGA pooled cohorts and most cancers. Consistently, in ICI-treated cohorts, patients with high PDL2 expression experienced longer overall survival time (OS) and were more likely responsive to ICIs than patients with low PDL2 expression. Immune cell scores of the high PDL2 expression patients were significantly higher (P < 0.05) than those of the low PDL2 expression patients in ICI-treated cohorts. In conclusion, our findings suggest that PDL2 is a potential predictive biomarker for ICIs.