Evaluating the Prognostic Role of the PAM50 Signature and Selected Immune-Related Signatures for Recurrence in Patients With T1abN0 Breast Cancer.

BACKGROUND: De-escalation of adjuvant treatment in patients with T1abN0 breast cancer is discussed internationally. Identification of new prognostic factors in these patients may assist this de-escalation. The PAM50 signature and tumor inflammation signature (TIS), Programmed Cell Death Protein 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) signatures are possible prognostic factors for recurrence. MATERIALS AND METHODS: Danish patients with T1abN0 breast cancer diagnosed between 2007-2016 were identified, the NanoString Breast Cancer 360 Panel was performed on tissue samples from cases with recurrence matched 1:1 with controls without recurrence (n = 234). The association between gene signatures and recurrence was analyzed with conditional logistic regression. RESULTS: Patients with the basal-like subtype had higher values of TIS, PD-1 and PD-L1 scores compared with other subtypes. Patients with higher PD-L1 score had significantly lower odds of recurrence (odds ratio [OR] 0.61, P = .01). Likewise, an increased TIS score was associated to lower, but nonsignificant odds of recurrence (OR 0.76, P = .07). Patients with human epidermal growth factor receptor 2 (HER2)-enriched subtype had significantly higher odds of recurrence compared with patients with luminal A subtype (OR 4.8, P = .03). DISCUSSION: PAM50 and immune-related signatures provide important prognostic information in patients with T1abN0 breast cancer, which may refine the risk assessment in these patients.

HIPK2 in Colon Cancer: A Potential Biomarker for Tumor Progression and Response to Therapies.

Colon cancer, one of the most common and fatal cancers worldwide, is characterized by stepwise accumulation of specific genetic alterations in tumor suppressor genes or oncogenes, leading to tumor growth and metastasis. HIPK2 (homeodomain-interacting protein kinase 2) is a serine/threonine protein kinase and a "bona fide" oncosuppressor protein. Its activation inhibits tumor growth mainly by promoting apoptosis, while its inactivation increases tumorigenicity and resistance to therapies of many different cancer types, including colon cancer. HIPK2 interacts with many molecular pathways by means of its kinase activity or transcriptional co-repressor function modulating cell growth and apoptosis, invasion, angiogenesis, inflammation and hypoxia. HIPK2 has been shown to participate in several molecular pathways involved in colon cancer including p53, Wnt/ß-catenin and the newly identified nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2). HIPK2 also plays a role in tumor-host interaction in the tumor microenvironment (TME) by inducing angiogenesis and cancer-associated fibroblast (CAF) differentiation. The aim of this review is to assess the role of HIPK2 in colon cancer and the underlying molecular pathways for a better understanding of its involvement in colon cancer carcinogenesis and response to therapies, which will likely pave the way for novel colon cancer therapies.

Celastrus orbiculatus Extract Inhibits Immune Inflammatory Thrombotic State of B-Lymphoma.

OBJECTIVE: To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo. METHODS: The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg-1·d-1) and CTX (40 mg·kg-1·d-1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded. RESULTS: The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05). CONCLUSION: COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment.

Tumor metabolic crosstalk and immunotherapy.

Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.

Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells.

Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor-associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor-infiltrating immune cells. Although interleukin-32 (IL-32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin-32θ (IL-32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT-qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme-linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL-32θ on proliferation, migration, epithelial-mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL-32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro-inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL-32θ inhibited the expression of inflammatory factors by regulating the NF-κB pathway. Furthermore, mutated IL-32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL-32θ modulates breast cancer progression. Mutated IL-32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF-κB (p65/p50) and FAK-PI3K-GSK3 pathways.

Transcription Factor GLI1 Induces IL-6-Mediated Inflammatory Response and Facilitates the Progression of Adamantinomatous Craniopharyngioma.

Adamantinomatous craniopharyngioma (ACP) is a neuroendocrine tumor whose pathogenesis remains unclear. This study investigated the role of glioma-associated oncogene family zinc finger 1 (GLI1), a transcription factor in the sonic hedgehog (SHH) signaling pathway, in ACP. We discovered that GLI1 regulates the expression of IL-6, thereby triggering inflammatory responses in ACP and influencing the tumor's progression. Analyzing the Gene Expression Omnibus (GEO) database chip GSE68015, we found that GLI1 is overexpressed in ACP, correlating positively with the spite of ACP and inflammation markers. Knockdown of GLI1 significantly inhibited the levels of tumor necrosis factor α, interleukin-6 (IL-6), and IL-1ß in ACP cells, as well as cell proliferation and migration. We further identified a binding site between GLI1 and the promoter region of IL-6, demonstrating that GLI1 can enhance the expression of IL-6. These findings were verified in vivo, where activation of the SHH pathway significantly promoted GLI1 and IL-6 expressions in nude mice, inducing inflammation and tumor growth. Conversely, GLI1 knockdown markedly suppressed these processes. Our study uncovers a potential molecular mechanism for the occurrence of inflammatory responses and tumor progression in ACP.

Prostaglandin E2 in neuroblastoma: Targeting synthesis or signaling?

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor arising from neural crest cells of the developing sympathetic nervous system. Despite marked advances in cancer treatment, the survival rate of high-risk NB remains unsatisfactory. As a key pro-inflammatory mediator regulating tumor microenvironment, prostaglandin E2 (PGE2) promotes NB proliferation, angiogenesis, and immune evasion via acting on four G protein-coupled receptors, particularly the EP2 subtype. Recent studies have been vigorously focused on developing and evaluating compounds targeting PGE2-regulated tumor inflammation in animal models of NB. In this review, we revisit these translational efforts and examine the feasibility of pharmacological inhibition of enzymes responsible for PGE2 biosynthesis or its signaling receptors as emerging therapeutic strategies for NB. We also explore the potential downstream oncogenic pathways upon the activation of PGE2 receptors, aiming to bridge the knowledge gap between tumorigenesis and the role of elevated PGE2/EP2 signaling, which is widely observed in high-risk NBs.

Analysis of Genomic Alterations Associated with Recurrence in Early Stage HER2-Positive Breast Cancer.

We aimed to compare gene expression in primary tumors of patients with recurrence and nonrecurrence to gain insight into the biology of high-risk HER2-positive early breast cancer. Patients who underwent curative resection and received adjuvant trastuzumab for HER2-positive early breast cancer were evaluated. Gene expression analyses were performed using NanoString Technologies' nCounter Breast Cancer 360 Panel. PAM50 intrinsic subtypes and Breast Cancer Signatures including tumor inflammation signature (TIS) were evaluated. Of 247 patients, 28 (11.3%) had recurrence at a median follow-up of 54.2 months. Patients with pathological stage III, tumor size > 5 cm, axillary lymph node metastases, and hormone receptor-negativity were more frequently observed in the recurrent group compared with the nonrecurrent group. In patients with recurrence, seven genes were upregulated significantly, including WNT11, HAPLN1, FGF10, BBOX1, CXADR, NDP, and EREG, and two genes were downregulated, including CXCL9 and GNLY. TIS score was significantly lower in patients with recurrence compared with controls without recurrence. These findings suggest that activation of oncogenic signaling pathways related to cell proliferation, adhesion, cancer stemness, and noninflamed tumor microenvironment are associated with the risk of recurrence in early stage, HER2-positive breast cancer.

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity.

The standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas. Interventions aimed at targeting components of the tumor microenvironment have shown promise for many solid tumors yet have been only marginally tested for sarcoma, partly because knowledge of the sarcoma microenvironment composition is limited. We employ single-cell RNA sequencing to characterize the immune composition of an undifferentiated pleiomorphic sarcoma mouse model, showing that macrophages in the sarcoma mass exhibit distinct activation states. Sarcoma cells use the pleiotropic cytokine macrophage migration inhibitory factor (MIF) to interact with macrophages expressing the CD74 receptor to switch macrophages' activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care.

Withania somnifera - a magic plant targeting multiple pathways in cancer related inflammation.

BACKGROUND: Deregulated inflammatory responses are known to play a pivotal role in cancer initiation and progression. Tumor microenvironment is associated with the presence of a diverse array of inflammatory reactions, which further help tumor growth, metastasis and drug resistance. Withania somnifera is known to curb proliferation of cancer cells and lower inflammatory responses. PURPOSE: In order to minimize the inflammation, cancer treatments often include immunomodulatory drugs. However, given the side effects of both of the cytotoxic cancer drugs and synthetic immunomodulatory agents, there is a need to develop novel anti-inflammatory agents for improved cancer therapy. A number of reports indicate that bioactive phytochemicals derived from W. somnifera exhibit anti-inflammatory capabilities in cancer. A deeper look into the underlying molecular mechanisms implicated in W. somnifera mediated anti inflammation is lacking, which is essential to fully understand the potential of this magical plant in cancer. Therefore, in the present review we are summarizing various reports, which describe mechanistic understanding of W. somnifera in cancer related inflammation. STUDY DESIGN AND METHODOLOGY: In order to gather information on the molecular pathways affected by W. somnifera in cancer related inflammation, 'PubMed' and 'Science Direct' databases were searched using keywords Withania, cancer inflammation, and Withaferin A. Selected literature was analyzed to cover the role of inflammation in cancer, usage and side effects of anti-inflammatory drugs, W. somnifera as an immunomodulatory agent in cancer, molecular pathways modulated by W. somnifera in various preclinical models, and clinical trials using W. somnifera as an anti-inflammatory agent. RESULTS: Upon literature survey we found that both W. somnifera extracts and Withaferin-A, exhibit anti inflammatory activities in various preclinical cancer models. W. somnifera modulates a number of signaling pathways such as NF-kB, JAK-STAT and AP1 to reduce cancer related inflammation. Anti inflammatory properties of W. somnifera might be effective in the treatment of drug resistance in cancers. Based on its promising effects against cancer associated inflammation in preclinical studies, W. somnifera derived products are being tested in clinical trials. CONCLUSION: Several preclinical studies demonstrated anti-inflammatory potential of W. somnifera in a variety of cancers. While a few clinical trials are investigating the role of W. somnifera in various diseases, focused studies on its role in cancer related inflammation are lacking. Additionally, its anti-inflammatory effects offer targeting of senescence associated secretory phenotype (SASP), which is speculated to play a critical role in chemoresistance. Apart from targeting cancer cell proliferation, anti-inflammatory effects of Withania provide double advantage in cancer management. Therefore, clinical trials to target cancer related inflammation using W. somnifera as a drug, should be performed to validate its advantages in cancer therapy.

Biomimetic approaches for targeting tumor-promoting inflammation.

With the ultimate goal of increasing tumor accumulation of therapeutics, various nanocarriers have been designed to overcome biological barriers encountered at each stage, from drug administration to the cancerous lesion. Stabilizing circulation and functionalization of the targeting surface impart high tumor accumulation properties to nanocarriers. However, various cells can recognize and infiltrate the tumor microenvironment more efficiently than synthetic carriers via overexpression of adhesive ligands, particularly in inflamed stroma of tumors. Thus, a new field of nanomedicine, called biomimicry, has evolved to generate nanoparticles with the same biological characteristics as cells that naturally infiltrate tumors. Revolutionary synthetic processes have been developed to transfer the cell membrane of leukocytes and mesenchymal cells to synthetic carriers. In addition, cells can generate their own "nanocarriers," known as exosomes, to transport molecular messages to distant sites, while biomimicry of viral and bacterial agents allows high targeting efficiency towards inflammatory immune cells. Alterations in the protein expression in cancer cells caused by inflammation can also be exploited for drug delivery. Finally, new developments in biomimetic drug delivery focus on turning the infiltrating cells into microcarriers that can actively perfuse the tumor and eventually release their therapeutic payload. In this review, we summarize recent developments in biomimetic drug delivery with a particular focus on targeting the tumor inflammatory microenvironment.

The combination of immune checkpoint inhibitors and chemotherapy in advanced non-small-cell lung cancer: the rational choice.

Lung cancer is the second most common cancer worldwide and the leading cause of death among cancers. The progressive approvals of immunotherapy as first-line treatment options have helped improve cancer prognosis. However, longer follow-up has confirmed the possibility of acquired resistance to immune checkpoint inhibitors (ICIs) which can lead to late relapses. Chemotherapy can act as a priming therapy to increase a tumor's response to immunotherapy. We aim through this review to explain the mechanism behind ICI resistance and the value of chemotherapy in escaping this resistance. Finally, all US FDA approvals regarding the management of metastatic non-small-cell lung cancer using a combination of ICIs and chemotherapy are summarized.

Delta-5-desaturase: A novel therapeutic target for cancer management.

Delta-5 desaturase (D5D) is a rate-limiting enzyme that introduces double-bonds to the delta-5 position of the n-3 and n-6 polyunsaturated fatty acid chain. Since fatty acid metabolism is a vital factor in cancer development, several recent studies have revealed that D5D activity and expression could be an independent prognostic factor in cancers. However, the mechanistic basis of D5D in cancer progression is still controversial. The classical concept believes that D5D could aggravate cancer progression via mediating arachidonic acid (AA)/prostaglandin E2 production from dihomo-γ-linolenic acid (DGLA), resulting in activation of EP receptors, inflammatory pathways, and immunosuppression. On the contrary, D5D may prevent cancer progression through activating ferroptosis, which is iron-dependent cell death. Suppression of D5D by RNA interference and small-molecule inhibitor has been identified as a promising anti-cancer strategy. Inhibition of D5D could shift DGLA peroxidation pattern from generating AA to a distinct anti-cancer free radical byproduct, 8-hydroxyoctanoic acid, resulting in activation of apoptosis pathway and simultaneously suppression of cancer cell survival, proliferation, migration, and invasion. Hence, understanding the molecular mechanisms of D5D on cancer may therefore facilitate the development of novel therapeutical applications. Given that D5D may serve as a promising target in cancer, in this review, we provide an updated summary of current knowledge on the role of D5D in cancer development and potentially useful therapeutic strategies.

An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment.

Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature's ability to discern an immune "cold", hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.

Case Report: Immune Checkpoint Inhibitor-Induced Exuberant Tumor Inflammation With Accelerated Clinical Deterioration in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Nivolumab, an anti-PD-1 monoclonal antibody, markedly improved overall survival in advanced renal cell carcinoma (RCC). However, ICIs can rarely trigger massive inflammation, a phenomenon characterized by rapid acceleration in radiographic tumor growth, the mechanisms underlying which are largely unknown. We report three patients with metastatic RCC who experienced rapid radiographic progression and clinical deterioration following treatment with nivolumab. However, histological analysis revealed no viable cancer despite the evidence of radiological progression. Instead, extensive necrosis and lymphohistiocytic infiltration were noted, as described previously in patients with ICI-induced pseudoprogression. Based on these observations, we postulate that exuberant antitumor inflammatory responses may contribute to adverse clinical outcomes in some patients with ICI-induced radiographic progression. Prospective studies incorporating tumor biopsies may shed more light on this rare phenomenon.

Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity.

The involvement of inflammation in cancer progression has been the subject of research for many years. Inflammatory milieu and immune response are associated with cancer progression and recurrence. In different types of tumors, growth and metastatic phenotype characterized by the epithelial mesenchymal transition (EMT) process, stemness, and angiogenesis, are increasingly associated with intrinsic or extrinsic inflammation. Among the inflammatory mediators, prostaglandin E2 (PGE2) supports epithelial tumor aggressiveness by several mechanisms, including growth promotion, escape from apoptosis, transactivation of tyrosine kinase growth factor receptors, and induction of angiogenesis. Moreover, PGE2 is an important player in the tumor microenvironment, where it suppresses antitumor immunity and regulates tumor immune evasion, leading to increased tumoral progression. In this review, we describe the current knowledge on the pro-tumoral activity of PGE2 focusing on its role in cancer progression and in the regulation of the tumor microenvironment.

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC.

Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately reanalyzed. APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV-negative HNSCC samples. An APOBEC-enriched, HPV-negative subgroup was identified, that showed higher T-cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune-evasion pathways were also enriched in these tumors. Analysis of single-cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.

Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas.

BACKGROUND: Ubiquitination is an important molecular event in lung squamous cell carcinoma (LSCC), which currently is mainly studied in nonsmall cell lung carcinoma cell models but lacking of ubiquitination studies on LSCC tissues. Here, we presented the ubiquitinated protein profiles of LSCC tissues to explore ubiquitination-involved molecular network alterations and identify abnormally ubiquitinated proteins as useful biomarkers for predictive, preventive, and personalized medicine (PPPM) in LSCC. METHODS: Anti-ubiquitin antibody-based enrichment coupled with LC-MS/MS was used to identify differentially ubiquitinated proteins (DUPs) between LSCC and control tissues, followed by integrative omics analyses to identify abnormally ubiquitinated protein biomarkers for LSCC. RESULTS: Totally, 400 DUPs with 654 ubiquitination sites were identified,, and motifs A-X (1/2/3)-K* were prone to be ubiquitinated in LSCC tissues. Those DUPs were involved in multiple molecular network systems, including the ubiquitin-proteasome system (UPS), cell metabolism, cell adhesion, and signal transduction. Totally, 44 hub molecules were revealed by protein-protein interaction network analysis, followed by survival analysis in TCGA database (494 LSCC patients and 20,530 genes) to obtain 18 prognosis-related mRNAs, of which the highly expressed mRNAs VIM and IGF1R were correlated with poorer prognosis, while the highly expressed mRNA ABCC1 was correlated with better prognosis. VIM-encoded protein vimentin and ABCC1-encoded protein MRP1 were increased in LSCC, which were all associated with poor prognosis. Proteasome-inhibited experiments demonstrated that vimentin and MRP1 were degraded through UPS. Quantitative ubiquitinomics found ubiquitination level was decreased in vimentin and increased in MRP1 in LSCC. These findings showed that the increased vimentin in LSCC might be derived from its decreased ubiquitination level and that the increased MRP1 in LSCC might be derived from its protein synthesis > degradation. GSEA and co-expression gene analyses revealed that VIM and MRP1 were involved in multiple crucial biological processes and pathways. Further, TRIM2 and NEDD4L were predicted as E3 ligases to regulate ubiquitination of vimentin and MRP1, respectively. CONCLUSION: These findings revealed ubiquitinomic variations and molecular network alterations in LSCC, which is in combination with multiomics analysis to identify ubiquitination-related biomarkers for in-depth insight into the molecular mechanism and therapeutic targets and for prediction, diagnosis, and prognostic assessment of LSCC.

Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA).

The Tumor Inflammation Signature (TIS) is an investigational use only (IUO) 18-gene signature that measures a pre-existing but suppressed adaptive immune response within tumors. The TIS has been shown to enrich for patients who respond to the anti-PD1 agent pembrolizumab. To explore this immune phenotype within and across tumor types, we applied the TIS algorithm to over 9000 tumor gene expression profiles downloaded from The Cancer Genome Atlas (TCGA). As expected based on prior evidence, tumors with known clinical sensitivity to anti-programmed cell death protein 1 (PD-1) blockade had higher average TIS scores. Furthermore, TIS scores were more variable within than between tumor types, and within each tumor type a subset of patients with elevated scores was identifiable although with different prevalence associated with each tumor type, the latter consistent with the observed clinical responsiveness to anti PD-1 blockade. Notably, TIS scores only minimally correlated with mutation load in most tumors and ranking tumors by median TIS score showed differing association to clinical sensitivity to PD-1/PD-1 ligand 1 (PD-L1) blockade than ranking of the same tumors by mutation load. The expression patterns of the TIS algorithm genes were conserved across tumor types yet appeared to be minimally prognostic in most cancers, consistent with the TIS score serving as a pan-cancer measurement of the inflamed tumor phenotype. Characterization of the prevalence and variability of TIS will lead to increased understanding of the immune status of untreated tumors and may lead to improved indication selection for testing immunotherapy agents.

Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation.

Immune cells constantly survey the host for pathogens or tumors and secrete cytokines to alert surrounding cells of these threats. In vivo, activated immune cells secrete cytokines for several hours, yet an acute immune reaction occurs over days. Given these divergent timescales, we addressed how cytokine-responsive cells translate brief cytokine exposure into phenotypic changes that persist over long timescales. We studied melanoma cell responses to transient exposure to the cytokine interferon γ (IFNγ) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNγ is captured by phosphatidylserine (PS) on the surface of viable cells both in vitro and in vivo then slowly released to drive long-term transcription of cytokine-response genes. This mechanism introduces an additional function for PS in dynamically regulating inflammation across diverse cancer and primary cell types and has potential to usher in new immunotherapies targeting PS and inflammatory pathways.