Pro-tumor Effects Research Articles

The Role of Osteopontin in Tumor Progression Through Tumor-Associated Macrophages.

Osteopontin (OPN) is a multifunctional phosphorylated protein. It is widely involved in solid tumor progression, such as intensification of macrophage recruitment, inhibition of T-cell activity, aggravation of tumor interstitial fibrosis, promotion of tumor metastasis, chemotherapy resistance, and angiogenesis. Most of these pathologies are affected by tumor-associated macrophages (TAMs), an important component of the tumor microenvironment (TME). TAMs have been extensively characterized, including their subsets, phenotypes, activation status, and functions, and are considered a promising therapeutic target for cancer treatment. This review focuses on the interaction between OPN and TAMs in mediating tumor progression. We discuss the strategies for targeting OPN and TAMs to treat cancer and factors that may affect the therapeutic outcomes of blocking OPN or depleting TAMs. We also discuss the role of cancer cell- vs. TAM-derived OPN in tumorigenesis, the mechanisms of how OPN affects TAM recruitment and polarization, and why OPN could mediate anti-tumor and pro-tumor effects, as well as previously reported discrepancies.

ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain.

Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create an adenosine-rich immunosuppressive microenvironment through the increased release of ATP from dying and stressed cells and its ectoenzymatic conversion into adenosine. Therefore, the adenosine pathway becomes an important therapeutic target to improve the effectiveness of immune therapies. Prior research has focused largely on the two major ectonucleotidases, ectonucleoside triphosphate diphosphohydrolase 1/cluster of differentiation (CD)39 and ecto-5'-nucleotidase/CD73, which catalyze the breakdown of extracellular ATP into adenosine, and on the subsequent activation of different subtypes of adenosine receptors with mixed findings of antitumor and protumor effects. New findings, needed for more effective therapeutic approaches, require consideration of redundant pathways controlling intratumoral adenosine levels, including the alternative NAD-inactivating pathway through the CD38-ectonucleotide pyrophosphatase phosphodiesterase (ENPP)1-CD73 axis, the counteracting ATP-regenerating ectoenzymatic pathway, and cellular adenosine uptake and its phosphorylation by adenosine kinase. This review provides a holistic view of extracellular and intracellular adenosine metabolism as an integrated complex network and summarizes recent data on the underlying mechanisms through which adenosine and its precursors ATP and ADP control cancer immunosurveillance, tumor angiogenesis, lymphangiogenesis, cancer-associated thrombosis, blood flow, and tumor perfusion. Special attention is given to differences and commonalities in the purinome of different cancers, heterogeneity of the tumor microenvironment, subcellular compartmentalization of the adenosine system, and novel roles of purine-converting enzymes as targets for cancer therapy. SIGNIFICANCE STATEMENT: The discovery of the role of adenosine as immune checkpoint regulator in cancer has led to the development of novel therapeutic strategies targeting extracellular adenosine metabolism and signaling in multiple clinical trials and preclinical models. Here we identify major gaps in knowledge that need to be filled to improve the therapeutic gain from agents targeting key components of the adenosine metabolic network and, on this basis, provide a holistic view of the cancer purinome as a complex and integrated network.

Abstract 1600: Dose-dependent effects of interferon-gamma treatment on pancreatic ductal adenocarcinoma cell states

Abstract Interferon-gamma (IFNγ) is a canonical proinflammatory cytokine that has well-studied antitumor functions such as the upregulation of MHC Class I (MHC-I), increased Th1 development, macrophage activity, innate immune cell recruitment, and in tumor cells increased apoptosis, decreased angiogenesis and proliferation. However, IFNγ is also important in limiting tissue destruction due to inflammation, taking on an immunotolerant role and allowing cancer cells to evade immune surveillance. We previously identified an interferon response cell state across diverse cancer types, as defined by the relative expression of IFIT1, HLA-A, HLA-DRA, STAT1, and IRF1. The interferon response cell state is heterogeneously expressed in cancer cells and appears to function both by cancer cell extrinsic and intrinsic mechanisms. Several clinical trials have tested the efficacy of IFNγ as a therapeutic for immune system stimulation in patients with melanoma. However, these have failed to detect effective outcomes, and have even noted some pro-growth actions, perhaps consistent with IFNγ’s immunotolerant role in maintaining tissue homeostasis. We are interested in identifying cell populations that are vulnerable to the antitumor functions of IFNγ, as well as cell populations that may be susceptible to IFNγ’s pro-tumor actions. To test this, we treated a pancreatic ductal adenocarcinoma cell line with three doses of IFNγ in vitro every day for five days and analyzed expression of proteins associated with IFNγ signaling by flow cytometry each day. Distinct doses of IFNγ have been shown to affect varying degrees of antitumor and pro-tumor responses. For example, growth inhibition has been seen upon treatment with high dose IFNγ, while treatment with low dose IFNγ is consistent with increased metastatic capability such as increased resistance to cytotoxic lymphocytes and natural killer cells despite the upregulation of MHC-I. We thus treated cells with three doses of IFNγ: low, normal, and high. Preliminary results have shown a dose dependent effect of IFNγ including the upregulation of MHC-I and PDL1. Ongoing work includes identifying changes in cell states using single-cell RNA-sequencing to uncover how cancer cells respond to varying intensities of IFNγ exposure. Additionally, we are analyzing how release of IFNγ from cancer cells changes following treatment of IFNγ at different doses. This work will provide insight into the mechanisms by which cancer cells evade immune surveillance and how cell states can describe a tumor’s vulnerability to IFNγ’s antitumor and pro-tumor effects. Citation Format: Deborah A. Liberman, Dalia Barkley, Itai Yanai. Dose-dependent effects of interferon-gamma treatment on pancreatic ductal adenocarcinoma cell states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1600.

Abstract 3136: Molecular characterization of the effects of cancer-derived exosomes on murine lung cancer tumors

Abstract Lung cancer is the second most diagnosed type of cancer and is the leading cause of cancer-related deaths in both men and women. An estimated 235,760 new cases of lung cancer and 131,880 lung cancer deaths are expected this year accounting for 12% of new cancer cases and 22% of cancer deaths in the United States. Exosomes are secreted vesicles that contain selectively packaged biomaterials (protein, lipids, and RNA) and serve as a form of extracellular communication between cells in the tumor microenvironment. Previous studies have shown the effects of cancer-derived exosomes on specific cell types or gross tumor response in vivo yet, the competitive nature and dynamics of exosomal uptake in the tumor microenvironment remains largely unknown. This work seeks to identify molecular responses induced by cancer-derived exosomes on cells residing in the tumor microenvironment. In order to control tumor cell exposure to cancer-derived exosomes, heterogeneous ex vivo cultures derived from subcutaneous Lewis lung carcinoma (LLC) tumors in C57BL6 mice were exposed to fluorescently dyed LLC exosomes for up to 72 hours. Flow cytometric analysis was performed to identify preferential uptake of cancer exosomes into the stromal subpopulations of tumor cells. Increased uptake was observed throughout the duration of the exposure and preferential uptake was observed into neutrophils, macrophages, and endothelial cells while cancer cells, fibroblasts, and lymphocytes were underrepresented in the exosome uptaken population. Additionally, single cell RNA-sequencing was performed 24 hours post-exosomal exposure to identify transcriptional changes promoted by cancer exosome uptake. We found tumor-derived cancer cells to up-regulate transcripts associated with proliferation and down-regulated genes associated with interferon signaling in response to exosome uptake. These preliminary findings suggest that cancer-derived exosomes have targeted effects on specific cell types in the tumor microenvironment. Specifically in cancer cells, exosomal uptake can elicit protumor (cancer proliferation and immune suppression via decreased interferon signaling) effects that may serve as mediators of disease progression. An understanding of both cancer and host-derived exosomal response to disease progression may identify novel biomarkers and potential therapeutic targets previously undiscovered using canonical discovery methods. This study received funding from LLNL LDRD grant 21-LW-028. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344). LLNL-ABS-829271 Citation Format: Nicholas R. Hum, Nicole F. Leon, Aimy Sebastian, Kelly A. Martin, Gabriela G. Loots. Molecular characterization of the effects of cancer-derived exosomes on murine lung cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3136.

Abstract 1124: The identification and characterization of a novel A3R agonist with potent anti-cancer properties

Abstract Introduction: G protein-coupled receptors (GPCRs) are among the most druggable targets. Adenosine receptors (ARs) belong to the class A GPCRs. The role of adenosine and ARs in tumorigenesis is increasingly appreciated. Moreover, novel studies also point out pro-tumor and anti-tumor effects of modulating ARs. Besides A2AR and A2BR in immune-oncology, A3R was shown to be overexpressed in tumor tissue and play an important role in cancer. Especially A3R agonists decrease proliferation, induce cell cycle arrest and cytotoxicity selectively in cancer cells. However, most compounds fail in clinical trials due to their insufficient efficacy or high occurrence of adverse effects. Here we introduce a novel A3R agonist with plausible anti-cancer properties. Material and methods: First, we developed a screening pipeline of AR agonists and antagonists, where the hits from the primary screen (aequorin luminescence assay) were evaluated in the counter-screen (calcium mobilization assay) and confirmed in concentration-response experiments. In parallel, the identified modulators were subjected to cytotoxicity screening against a panel of tumor and non-tumor cell lines. The selected lead compound with potent anti-cancer properties was biologically and pharmacologically compared to a reference A3R agonist, 2-Cl-IB-MECA, recently evaluated in a clinical trial against hepatocellular carcinoma. To assess the relevance of the in vitro assays, the lead compound was administered to mice and its in vivo efficacy was evaluated. Results: Our screening pipeline shows high reproducibility and robustness. We identified several potential hits among the newly synthesized nucleosides and selected an A3R agonist PNH173 with significant cytotoxic effects against several tumor cell types compared to the reference A3R agonist. PNH173 also demonstrates good pharmacological properties in non-clinical ADME tests, reduces tumor growth, and increases overall survival in vivo experiments. Conclusions: We set out to identify novel small molecule A3R agonists with strong anti-tumor effects using a screening campaign and subsequent series of biological assays. Our data indicate desired anti-cancer properties of a novel A3R agonist PNH173 in in vitro and in vivo experiments, with higher efficacy compared to the reference compound. In addition, PNH173 demonstrates biased signaling which could be further utilized against human malignancies. Funding: The European Regional Development Fund (Project ENOCH No. CZ.02.1.01/0.0/0.0/16_019/0000868), the Czech Ministry of Education, Youth and Sports (EATRIS-CZ, LM2018133, and CZ-OPENSCREEN, LM2018130), the Czech Science Foundation (GACR 19-08124S), the Technology Agency of the Czech Republic: Czech National Centres of Competence, project “PerMed” Personalized Medicine - Diagnostics and Therapy (TN01000013), and the Grant agency of Palacky University (IGA_LF_2021_036). Citation Format: Jana Kotulova, Sona Gurska, Barbora Liskova, Miroslav Popper, Katerina Jecmenova, Petr Dzubak, Marian Hajduch. The identification and characterization of a novel A3R agonist with potent anti-cancer properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1124.

Abstract 6092: The dual roles of C-X-C MOTIF chemokine LIGAND 10 in pediatric osteosarcoma

Abstract Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of multi-agents chemotherapy and aggressive surgery, the survival of patients with osteosarcoma remains at 60% over the past three decades. In addition, the survival of patients who develop metastasis is dismal and often less than 25%. We have previously reported that serum C-X-C motif chemokine ligand 10 (CXCL10) is associated with survival in a large cohort of osteosarcoma patients. CXCL10 is an interferon-induced chemokine that binds to its cognate receptor CXCR3 to elicit its cellular effects via both autocrine and paracrine signaling. CXCL10 can promote tumor cell migration and metastasis via autocrine signaling, while it recruits CXCR3+ immune cells to exert a tumoricidal effect via paracrine signaling. However, little is known about the effect of circulating CXCL10 in cancer. To understand the role of CXCL10 in the pediatric bone tumor, we showed that a number of osteosarcoma cell lines expressed the CXCR3 protein. The addition of exogenous CXCL10 promoted tumor cell migration of three osteosarcoma cell lines but did not affect cell proliferation. However, the migratory effect of osteosarcoma cells is not specific to CXCL10, as other CXCR3-associated chemokines (CXCL4, CXCL9, and CXCL10) exerted similar effects. Using an orthotopic xenograft mouse model, we demonstrated intravenous injection of CXCL10 increased the development of pulmonary metastases of osteosarcoma. In contrast, expression profiling of osteosarcoma primary tumors showed that elevated expression of CXCL10 and CXCR3 was associated with a better prognosis, suggesting that a paracrine effect of CXCL10 by recruiting CXCR3+ immune cells to the tumor site. This notion is supported by our immune cell population deconvolution results, indicating that the predominant infiltrating immune cell types are macrophages and CD8+ T cells. Taken together, our results suggest a model in which CXCL10 may play both pro-tumor and anti-tumor roles in osteosarcoma. While a high level of exogenous or circulating CXCL10 may promote tumor cell migration and metastasis, the chemokine can also recruit CXCR3+ immune cells to exert a favorable prognostic effect. Further characterization of the sources of CXCL10 in the tumor site and circulation may lead to the development of a therapeutic approach that promotes CXCL10’s anti-tumor effects and minimizes its pro-tumor effects to improve the survival of osteosarcoma patients. Citation Format: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man. The dual roles of C-X-C MOTIF chemokine LIGAND 10 in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6092.

Abstract 2088: ATLAS-identified Inhibigen-specific responses accelerate tumor growth in mouse melanoma and pancreatic cancer

Abstract Genocea’s ATLAS platform is an empirical bioassay that uses patient autologous immune cells to identify both true neoantigens and Inhibigens࣪ for inclusion in or exclusion from neoantigen-targeted vaccines and cell therapies, respectively. In ATLAS, patient-derived antigen-presenting cells (APCs) are pulsed with E. coli expressing individual mutations identified from the patient mutanome ± listeriolysin O, enabling interrogation of both CD8+ and CD4+ T cell recognition. True neoantigens induce T cell activation and cytokine release, while Inhibigens lead to a downregulation of T cell responses and thus can promote tumor growth. Previous ATLAS screening of CD8+ T cells from mice carrying B16F10 mouse melanoma tumors identified both neoantigens and Inhibigens. Upon therapeutic vaccination, adjuvanted neoantigens generated immunogenicity and anti-tumor efficacy1. In contrast, therapeutic vaccination with multiple ATLAS-identified Inhibigens, alone or in combination with an otherwise-protective vaccine, led to accelerated tumor growth, impaired T cell responses, and abrogated tumor immune infiltration. Our current study further explores the mechanism of Inhibigen-specific responses through adoptive transfer of vaccine-experienced T cells into tumor-bearing recipient mice, as well as through analysis of T cell gene expression. Additionally, in order to determine whether Inhibigen identification and treatment translates into pro-tumor effects universally across tumor models, we performed ATLAS screening on CD4+ and CD8+ T cells isolated from mice bearing orthotopic KPC pancreatic cancer. Out of 73 total non-synonymous mutations, we successfully identified 14 CD4+ and 15 CD8+ true neoantigens, and 16 CD4+ and 18 CD8+ Inhibigens. This is the first known comprehensive characterization of endogenous antigens in this model. Therapeutic administration of neoantigens as adjuvanted peptide vaccines in KPC tumor-bearing mice led to smaller tumor sizes and reduced ascites volumes, whereas Inhibigen vaccination accelerated tumor growth. Mouse studies are ongoing and additional data will be presented. Taken together, our data from human cancer patients and two mouse cancer models support the importance of appropriate neoantigen selection and Inhibigen identification and exclusion from cancer therapies. Genocea’s GEN-011 neoantigen-targeted peripheral T cell (NPT) therapy candidate, designed using ATLAS-identified neoantigens and omitting Inhibigens, is being evaluated in an ongoing clinical trial (NCT04596033). Continued exploration of mechanisms of action of Inhibigen-specific responses may reveal new paradigms of cancer immune evasion. 1H Lam et al, Cancer Discov 2021;11:1-18 Citation Format: Hanna S. Starobinets, Victoria L. DeVault, Zoe C. Schmiechen, Ebony A. Miller, Eduardo Cruz, Meagan R. Rollins, Adam L. Burrack, Stephanie J. Rinaldi, Julie Arnold, Emily Tjon, Kyle Gonzalez, Dimitry Lineker, Hubert Lam, Ingunn M. Stromnes, Jessica B. Flechtner. ATLAS-identified Inhibigen-specific responses accelerate tumor growth in mouse melanoma and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2088.

Microbial-Derived Toll-like Receptor Agonism in Cancer Treatment and Progression

Simple SummaryToll like receptors (TLRs) are a group of transmembrane receptors belonging to the class of pattern recognition receptors (PRR), which are involved in recognition of pathogen associated molecular patterns (PAMPs), inducing immune response. During the past decade, a number of preclinical and clinical breakthroughs in the field of TLR agonists has immerged in cancer research and some of these agents have performed exceptionally well in clinical trials. Based on evidence from scientific studies, we draw attention to several microbial based TLR agonists and discuss their relevance in various cancer and explore various microbial based TLR agonists for developing effective immunotherapeutic strategies against cancer.Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection.

Tumor-Associated Inflammation: The Tumor-Promoting Immunity in the Early Stages of Tumorigenesis.

Tumorigenesis is a multistage progressive oncogenic process caused by alterations in the structure and expression level of multiple genes. Normal cells are continuously endowed with new capabilities in this evolution, leading to subsequent tumor formation. Immune cells are the most important components of inflammation, which is closely associated with tumorigenesis. There is a broad consensus in cancer research that inflammation and immune response facilitate tumor progression, infiltration, and metastasis via different mechanisms; however, their protumor effects are equally important in tumorigenesis at earlier stages. Previous studies have demonstrated that during the early stages of tumorigenesis, certain immune cells can promote the formation and proliferation of premalignant cells by inducing DNA damage and repair inhibition, releasing trophic/supporting signals, promoting immune escape, and activating inflammasomes, as well as enhance the characteristics of cancer stem cells. In this review, we focus on the potential mechanisms by which immune cells can promote tumor initiation and promotion in the early stages of tumorigenesis; furthermore, we discuss the interaction of the inflammatory environment and protumor immune cells with premalignant cells and cancer stem cells, as well as the possibility of early intervention in tumor formation by targeting these cellular mechanisms.

Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer.

Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.

The Role of Exosomes in the Progression and Therapeutic Resistance of Hematological Malignancies.

Exosomes are membrane limited structures which derive from cell membranes and cytoplasm. When released into extracellular space, they circulate through the extracellular fluid, including the peripheral blood and tissue fluid. Exosomes surface molecules mediate their targeting to specific recipient cells and deliver their contents to recipient cells by receptor-ligand interaction and/or phagocytosis and/or endocytosis or direct fusion with cell membrane. Exosomes contain many functional molecules, including nucleic acids (DNAs, mRNAs, non-coding RNAs), proteins (transcription factors, enzymes), and lipids which have biological activity. By passing these cargos, exosomes can transfer information between cells. In this way, exosomes are extensively involved in physiological and pathological processes, such as angiogenesis, matrix reprogramming, coagulation, tumor progression. In recent years, researcher have found that exosomes from malignant tumors can mediate information exchange between tumor cells or between tumor cells and non-tumor cells, thereby promoting tumor survival, progression, and resistance to therapy. In this review, we discuss the pro-tumor and anti-therapeutic effects of exosomes in hematological malignancies, hoping to contribute to the early conquest of hematological malignancy.

The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis.

Simple SummaryExtracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.

Noncanonical PD-1/PD-L1 Axis in Relation to the Efficacy of Anti-PD Therapy.

With programmed death 1/ligand 1 (PD-1/PD-L1) as the cornerstone, anti-PD antibodies have pioneered revolutionary immunotherapies for malignancies. But most patients struggled to respond to anti-PD owing to primary or acquired resistance or even hyperprogression, pointing to more efforts needed to explore this axis. PD-1 constrains T-cell immunoreactivity via engaging with PD-L1 of tumor/myeloid cells is the canonical PD-1/PD-L1 axis function mode. Studies are increasingly aware of the impact of noncanonical PD-1/PD-L1 expression in various cancers. PD-L1 induced on activated T-cells ligates to PD-1 to mediate self-tolerance or acts on intratumoral myeloid cells and other T-cells, affecting their survival, differentiation and immunophenotyping, leading to tumor immunosuppression. Myeloid PD-1 interferes with their proliferation, differentiation, cytokine secretion and phagocytosis, mediating remarkable pro-tumor effects. Tumor cell intrinsic PD-1 signaling has diverse functions in different tumors, resulting in pro-proliferation or proliferation inhibition. These nonclassical PD-1/PD-L1 functions may be novel anti-PD mechanisms or causes of treatment resistance. This review highlights the nonnegligible role of T-cell-intrinsic PD-L1 and tumor/myeloid PD-1 in the cell interplay network and the complex impact on the efficacy of anti-PD antibodies. Reconsidering and rational utilization of the comprehensive PD-1/PD-L1 axis could cumulate breakthroughs in precision treatment and combination for anti-PD therapies.

ENO3 promotes colorectal cancer progression by enhancing cell glycolysis.

Colorectal cancer (CRC) is among the leading cause of cancer-related morbidity and mortality worldwide. Aerobic glycolysis, as a metabolic hallmark of cancer, plays an important role in CRC progression. Enolase 3 (ENO3) is a glycolytic enzyme that catalyzes 2-phosphoglycerate into phosphoenolpyruvate, while its role in CRC is still unknown. Bioinformatics analysis was performed to examine the expression changes and roles of ENO3 in CRC patients from public databases. Then, ENO3 expression was validated in CRC tissues using Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis, and western blot. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. Cell viability, proliferation, and migration in vitro were applied to evaluate the protumoral effects of ENO3 on CRC. RNA sequencing and GO enrichment analysis of differentially expressed genes (DEGs) were performed to explore the underlying molecular mechanisms of ENO3 in CRC progression. The ATP and lactate production level were detected to assess cell glycolysis. ENO3 was significantly up-regulated in CRC. High ENO3 expression was positively correlated with poor prognosis and higher clinical stages of CRC patients. ROC curve demonstrated the diagnostic value of ENO3 for CRC with the AUC of 0.802. Gain- and loss-of function experiments demonstrated that ENO3 significantly enhanced the proliferation and migration ability of CRC cells in vitro. After ENO3 knockdown, RNA sequencing screened out a list of DEGs which were enriched in the regulation of the glycolytic process. The detection of lactate production and ATP level verified the role of ENO3 in the glycolytic process. Our findings illustrate that ENO3 could promote the progression of CRC by the enhancement of cell glycolysis, indicating the potential value of ENO3 as a novel biomarker and therapeutic target for CRC.

Activation of YAP1 by STK25 contributes to the progression of hepatocellular carcinoma

A pathogenic role of serine/threonine protein kinase 25 (STK25) has been observed in several chronic liver diseases. However, whether STK25 participates in hepatocellular carcinoma (HCC) remains unexplored. The current work aimed to explore the role and mechanism of STK25 in HCC. A high STK25 level was found in HCC tissue, which was associated with reduced overall survival. HCC cells with STK25 silencing displayed a marked decrease in proliferative and invasive ability, but were highly sensitive to apoptosis induced by the chemotherapy drug sorafenib. Reciprocally, HCC cells with forced expression of STK25 displayed the opposite effects. Further data unveiled that STK25 silencing restrained the activation of Yes-associated protein 1 (YAP1) associated with regulation of mammalian STE20-like protein kinase 1/2 (MST1/2). Forced expression of constitutively active YAP1 abolished STK25 silencing-induced antitumor effects, while repression of YAP1 reversed STK25 upregulation-induced protumor effects. Additionally, HCC cells with STK25 silencing exhibited reduced tumorigenic potential in vivo. Collectively, the results show that STK25 exerts a protumor function in HCC by enhancing YAP1 activation via regulation of MST1/2. These findings propose STK25 as a viable target for the development of anti-HCC therapy.

Redefining CD56 as a Biomarker and Therapeutic Target in Multiple Myeloma.

Multiple myeloma is an incurable, genetically heterogeneous disease, without available tailored therapeutic approaches. CD56 signaling promotes multiple myeloma growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing patients with multiple myeloma.

Harnessing the Anti-Tumor Mediators in Mast Cells as a New Strategy for Adoptive Cell Transfer for Cancer.

The emergence of cancer immunotherapies utilizing adoptive cell transfer (ACT) continues to be one of the most promising strategies for cancer treatment. Mast cells (MCs) which occur throughout vascularized tissues, are most commonly associated with Type I hypersensitivity, bind immunoglobin E (IgE) with high affinity, produce anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), and generally populate the tumor microenvironments. Yet, the role of MCs in cancer pathologies remains controversial with evidence for both anti-tumor and pro-tumor effects. Here, we review the studies examining the role of MCs in multiple forms of cancer, provide an alternative, MC-based hypothesis underlying the mechanism of therapeutic tumor IgE efficacy in clinical trials, and propose a novel strategy for using tumor-targeted, IgE-sensitized MCs as a platform for developing new cellular cancer immunotherapies. This autologous MC cancer immunotherapy could have several advantages over current cell-based cancer immunotherapies and provide new mechanistic strategies for cancer therapeutics alone or in combination with current approaches.

A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs.

BackgroundNecroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs.MethodsThe three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients.ResultsSeven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A.ConclusionsWe constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients.

M1 Macrophages Enhance Survival and Invasion of Oral Squamous Cell Carcinoma by Inducing GDF15-Mediated ErbB2 Phosphorylation.

M2 macrophages are generally recognized to have a protumor role, while the effect of M1 macrophages in cancer is controversial. Here, the in vitro and in vivo effects of conditioned medium from M1 macrophages (M1-CM) on oral squamous cell carcinoma (OSCC) cells and a potential mechanism were studied. CCK-8, colony formation, EdU labeling, xenograft growth, and Transwell assays were utilized to observe cell survival/proliferation and migration/invasion, respectively, in OSCC cell lines treated with basic medium (BM) and M1-CM. The ErbB2 phosphorylation inhibitor (CI-1033) and GDF15 knockout cell lines were used to appraise the role of ErbB2 and GDF15 in mediating the effects of M1-CM. Compared with BM, M1-CM significantly enhanced the survival/proliferation of SCC25 cells. The migration/invasion of SCC25 and CAL27 cells also increased. Mechanically, M1-CM promoted GDF15 expression and increased the phosphorylation of ErbB2, AKT, and ErK. CI-1033 significantly declined the M1-CM-induced activation of p-AKT and p-ErK and its protumor effects. M1-CM stimulated enhancement of p-ErbB2 expression was significantly decreased in cells with GDF15 gene knockout vs without. In xenograft, M1-CM pretreatment significantly promoted the carcinogenic potential of OSCC cells. Our results demonstrate that M1 macrophages induce the proliferation, migration, invasion, and xenograft development of OSCC cells. Mechanistically, this protumor effect of M1 macrophages is partly associated with inducing GDF15-mediated ErbB2 phosphorylation.

Connecting the Dots Between the Gut-IGF-1-Prostate Axis: A Role of IGF-1 in Prostate Carcinogenesis.

Prostate cancer (PCa) is the most common malignancy in men worldwide, thus developing effective prevention strategies remain a critical challenge. Insulin-like growth factor 1 (IGF-1) is produced mainly in the liver by growth hormone signaling and is necessary for normal physical growth. However, several studies have shown an association between increased levels of circulating IGF-1 and the risk of developing solid malignancies, including PCa. Because the IGF-1 receptor is overexpressed in PCa, IGF-1 can accelerate PCa growth by activating phosphoinositide 3-kinase and mitogen-activated protein kinase, or increasing sex hormone sensitivity. Short-chain fatty acids (SCFAs) are beneficial gut microbial metabolites, mainly because of their anti-inflammatory effects. However, we have demonstrated that gut microbiota-derived SCFAs increase the production of IGF-1 in the liver and prostate. This promotes the progression of PCa by the activation of IGF-1 receptor downstream signaling. In addition, the relative abundance of SCFA-producing bacteria, such as Alistipes, are increased in gut microbiomes of patients with high-grade PCa. IGF-1 production is therefore affected by the gut microbiome, dietary habits, and genetic background, and may play a central role in prostate carcinogenesis. The pro-tumor effects of bacteria and diet-derived metabolites might be potentially countered through dietary regimens and supplements. The specific diets or supplements that are effective are unclear. Further research into the “Gut–IGF-1–Prostate Axis” may help discover optimal diets and nutritional supplements that could be implemented for prevention of PCa.