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Oncolytic vaccinia viruses (VVs) are potent stimulators of the immune system and induce immune-mediated tumor clearance and long-term surveillance against tumor recurrence. As such they are ideal treatment modalities for solid tumors including lung cancer. Here, we investigated the use of VVL-m12, a next-generation, genetically modified, interleukin-12 (IL-12)-armed VV, as a new therapeutic strategy to treat murine models of lung cancer and as a mechanism of increasing lung cancer sensitivity to antibody against programmed cell death protein 1 (α-PD1) therapy. The cytotoxicity and replication of VVL-m12, VVL-h12 and control VVs were assessed in lung cancer cell lines. Subcutaneous lung cancer mouse models were established to investigate the anti-tumor activity of the viruses after intratumoral delivery in an immunocompetent disease model. Synergy with α-PD1 or a VV armed with soluble PD-1 (VV-sPD1) was investigated and functional mechanisms behind efficacy probed. Tumor-targeted VVL-m12 replicated to high levels, was cytotoxic in lung cancer cell lines. VVL-m12 demonstrated superior antitumor efficacy in subcutaneous lung cancer models compared with other VVs examined. Importantly, rational combination of VVL-m12 and PD-1 blockade worked synergistically to significantly enhance survival of animals and safely cured lung cancer with no evidence of recurrence. VVL-m12 therapy induced increased intratumoral infiltration of CD4+ and CD8+ T cells and was able to clear tumor at early time points via increased induction and infiltration of effector T cells and central memory T cells (TCM). In addition, VVL-m12 increased dendritic cell activation, induced polarization of M2 macrophages towards an M1 phenotype, and inhibited tumor angiogenesis in vivo. These results demonstrate that VVL-12 has strong potential as a safe and effective antitumor therapeutic for lung cancer. Importantly, VVL-12 can sensitize lung cancers to α-PD1 antibody therapy, and the combined regime creates a highly effective treatment option for patients. [ABSTRACT FROM AUTHOR]

Modest response rates to immunotherapy observed in advanced lung cancer patients underscore the need to identify reliable biomarkers and targets, enhancing both treatment decision-making and efficacy. Factors such as PD-L1 expression, tumor mutation burden, and a 'hot' tumor microenvironment with heightened effector T cell infiltration have consistently been associated with positive responses. In contrast, the predictive role of the abundantly present tumor-infiltrating myeloid cell (TIMs) fraction remains somewhat uncertain, partly explained by their towering variety in terms of ontogeny, phenotype, location, and function. Nevertheless, numerous preclinical and clinical studies established a clear link between lung cancer progression and alterations in intra- and extramedullary hematopoiesis, leading to emergency myelopoiesis at the expense of megakaryocyte/erythroid and lymphoid differentiation. These observations affirm that a continuous crosstalk between solid cancers such as lung cancer and the bone marrow niche (BMN) must take place. However, the BMN, encompassing hematopoietic stem and progenitor cells, differentiated immune and stromal cells, remains inadequately explored in solid cancer patients. Subsequently, no clear consensus has been reached on the exact breadth of tumor installed hematopoiesis perturbing cues nor their predictive power for immunotherapy. As the current era of single-cell omics is reshaping our understanding of the hematopoietic process and the subcluster landscape of lung TIMs, we aim to present an updated overview of the hierarchical differentiation process of TIMs within the BMN of solid cancer bearing subjects. Our comprehensive overview underscores that lung cancer should be regarded as a systemic disease in which the cues governing the lung tumor-BMN crosstalk might bolster the definition of new biomarkers and druggable targets, potentially mitigating the high attrition rate of leading immunotherapies for NSCLC. [ABSTRACT FROM AUTHOR]

Pericytes, recognized as mural cells, have long been described as components involved in blood vessel formation, playing a mere supporting role for endothelial cells (ECs). Emerging evidence strongly suggests their multifaceted roles in tissues and organs. Indeed, pericytes exhibit a remarkable ability to anticipate endothelial cell behavior and adapt their functions based on the specific cells they interact with. Pericytes can be activated by pro-inflammatory stimuli and crosstalk with immune cells, actively participating in their transmigration into blood vessels. Moreover, they can influence the immune response, often sustaining an immunosuppressive phenotype in most of the cancer types studied. In this review, we concentrate on the intricate crosstalk between pericytes and immune cells in cancer, highlighting the primary evidence regarding pericyte involvement in primary tumor mass dynamics, their contributions to tumor reprogramming for invasion and migration of malignant cells, and their role in the formation of pre-metastatic niches. Finally, we explored recent and emerging pharmacological approaches aimed at vascular normalization, including novel strategies to enhance the efficacy of immunotherapy through combined use with anti-angiogenic drugs. [ABSTRACT FROM AUTHOR]

FLASH radiotherapy (FLASH-RT) is a novel radiotherapy approach based on the use of ultra-high dose radiation to treat malignant cells. Although tumours can be reduced or eradicated using radiotherapy, toxicities induced by radiation can compromise healthy tissues. The FLASH effect is the observation that treatment delivered at an ultra-high dose rate is able to reduce adverse toxicities present at conventional dose rates. While this novel technique may provide a turning point for clinical practice, the exact mechanisms underlying the causes or influences of the FLASH effect are not fully understood. The study presented here uses data collected from 41 experimental investigations (published before March 2024) of the FLASH effect. Searchable databases were constructed to contain the outcomes of the various experiments in addition to values of beam parameters that may have a bearing on the FLASH effect. An in-depth review of the impact of the key beam parameters on the results of the experiments was carried out. Correlations between parameter values and experimental outcomes were studied. Pulse Dose Rate had positive correlations with almost all end points, suggesting viability of FLASH-RT as a new modality of radiotherapy. The collective results of this systematic review study suggest that beam parameter qualities from both FLASH and conventional radiotherapy can be valuable for tissue sparing and effective tumour treatment. [ABSTRACT FROM AUTHOR]

FLASH-radiotherapy delivers a radiation beam a thousand times faster compared to conventional radiotherapy, reducing radiation damage in healthy tissues with an equivalent tumor response. Although not completely understood, this radiobiological phenomenon has been proved in several animal models with a spectrum of all kinds of particles currently used in contemporary radiotherapy, especially electrons. However, all the research teams have performed FLASH preclinical studies using industrial linear accelerator or LINAC commonly employed in conventional radiotherapy and modified for the delivery of ultrahigh-dose-rate (UHDRs). Unfortunately, the delivering and measuring of UHDR beams have been proved not to be completely reliable with such devices. Concerns arise regarding the accuracy of beam monitoring and dosimetry systems. Additionally, this LINAC totally lacks an integrated and dedicated Treatment Planning System (TPS) able to evaluate the internal dose distribution in the case of in vivo experiments. Finally, these devices cannot modify dose-time parameters of the beam relevant to the flash effect, such as average dose rate; dose per pulse; and instantaneous dose rate. This aspect also precludes the exploration of the quantitative relationship with biological phenomena. The dependence on these parameters need to be further investigated. A promising advancement is represented by a new generation of electron LINAC that has successfully overcome some of these technological challenges. In this review, we aim to provide a comprehensive summary of the existing literature on in vivo experiments using electron FLASH radiotherapy and explore the promising clinical perspectives associated with this technology. [ABSTRACT FROM AUTHOR]

Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These agelinked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer. [ABSTRACT FROM AUTHOR]

This study aimed to develop a suitable dosage form of volatile oil from wampee leaves and to explore its antibacterial mechanism in vitro. The chemical composition of the volatile oil from wampee leaves was determined by gas chromatography-mass spectrometry (GC-MS). Different microemulsion ratios were tested and their stabilities were investigated to determine the optimal ratio. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the wampee leaves volatile oil emulsion (WVOE) against Salmonella typhimurium (S. typhimurium) and Staphylococcus aureus (S. aureus) were determined using double-dilution and plate-counting methods, respectively. Morphological changes in these two bacteria were observed using scanning electron microscopy. Death, ultrastructural morphology, and biofilm formation were also assessed for S. aureus. Finally, we established an S. aureusinfected Lewis lung carcinoma (LLC) cell model to evaluate the protective effects of the volatile oil emulsion and the associated mechanisms. The volatile oil extracted from wampee leaves contained 37 compounds, of which 96.49% were aromatic hydrocarbons, terpenoids, and their oxygen-containing derivatives. The emulsion was most stable at 1:1 in the oil phase and 1:9 in the water phase. WVOE had poor antibacterial activity against S. typhimurium, but the MIC and MBC against S. aureus were 312.5 and 2,500 µg/mL, respectively. S. aureus survival rates were 84.6%, 14.5%, and 12.8% in the 1/2, 1, and 4 × MIC groups, respectively, compared with 97.2% in the control group. S. typhimurium survival was not affected by WVOE treatment. WVOE administration induced cavity formation and abnormal binary fission, and significantly inhibited biofilm formation in S. aureus cells. The WVOE notably reduced the number of S. aureus and inhibited TLR4, NLRP3, NF-κB, IL-6, IL-18, and TNF-a gene expression in S. aureus-infected LLC cells. The WVOE had a significant inhibitory effect on S. aureus and altered its cell membrane permeability. Moreover, it alleviated inflammation by inhibiting the NF-κB-NLRP3 pathway in S. aureus-infected LLC cells. [ABSTRACT FROM AUTHOR]

Lung cancer is a disease of global concern, and immunotherapy has brought lung cancer therapy to a new era. Besides promising effects in the clinical use of immune checkpoint inhibitors, immune-related adverse events (irAEs) and low response rates are problems unsolved. Natural products and traditional medicine with an immune-modulating nature have the property to influence immune checkpoint expression and can improve immunotherapy's effect with relatively low toxicity. This review summarizes currently approved immunotherapy and the current mechanisms known to regulate immune checkpoint expression in lung cancer. It lists natural products and traditional medicine capable of influencing immune checkpoints or synergizing with immunotherapy in lung cancer, exploring both their effects and underlying mechanisms. Future research on immune checkpoint modulation and immunotherapy combination applying natural products and traditional medicine will be based on a deeper understanding of their mechanisms regulating immune checkpoints. Continued exploration of natural products and traditional medicine holds the potential to enhance the efficacy and reduce the adverse reactions of immunotherapy. [ABSTRACT FROM AUTHOR]

In recent years, the relationship between lipid metabolism and tumour immunotherapy has been thoroughly investigated. An increasing number of studies have shown that abnormal gene expression and ectopic levels of metabolites related to fatty acid synthesis or fatty acid oxidation affect tumour metastasis, recurrence, and drug resistance. Tumour immunotherapy that aims to promote an antitumour immune response has greatly improved the outcomes for tumour patients. However, lipid metabolism reprogramming in tumour cells or tumour microenvironment-infiltrating immune cells can influence the antitumour response of immune cells and induce tumor cell immune evasion. The recent increase in the prevalence of obesity-related cancers has drawn attention to the fact that obesity increases fatty acid oxidation in cancer cells and suppresses the activation of immune cells, thereby weakening antitumour immunity. This article reviews the changes in lipid metabolism in cells in the tumour microenvironment and describes the relationship between lipid metabolism reprogramming in multiple cell types and tumour immunotherapy. [ABSTRACT FROM AUTHOR]

The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel cancer therapies that can provide clinical benefit for most patients with solid malignancies, which harbor innate or acquired resistance to ICIs. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy given its direct stimulatory effects on innate and adaptive immunity. However, unfavorable pharmacokinetics and a narrow therapeutic index render recombinant IL-12 (rIL-12) less attractive as a cancer therapy. NHSIL12 is a fusion protein of IL-12 and NHS76 (human IgG1) antibody engineered to target single and double stranded DNA present in necrotic areas solid tumors. In preclinical tumor models, NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated clinically in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. Here we review the preclinical and clinical studies involving NHS-IL12 for the treatment of solid malignancies. [ABSTRACT FROM AUTHOR]

The immune system plays a critical role in cancer, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Immunotherapy, particularly immune checkpoint blockade, has revolutionized the treatment of lung cancer, but a large subset of patients either do not respond or develop resistance. Exosomes, essential mediators of cell-to-cell communication, exert a profound influence on the tumor microenvironment and the interplay between cancer and the immune system. This review focuses on the role of tumorderived exosomes and immune cells-derived exosomes in the crosstalk between these cell types, influencing the initiation and progression of lung cancer. Depending on their cell of origin and microenvironment, exosomes can contain immunosuppressive or immunostimulatory molecules that can either promote or inhibit tumor growth, thus playing a dual role in the disease. Furthermore, the use of exosomes in lung cancer immunotherapy is discussed. Their potential applications as cell-free vaccines and drug delivery systems make them an attractive option for lung cancer treatment. Additionally, exosomal proteins and RNAs emerge as promising biomarkers that could be employed for the prediction, diagnosis, prognosis and monitoring of the disease. In summary, this review assesses the relationship between exosomes, lung cancer, and the immune system, shedding light on their potential clinical applications and future perspectives. [ABSTRACT FROM AUTHOR]

The kynurenine pathway (KP) and associated catabolites play key roles in promoting tumor progression and modulating the host anti-tumor immune response. To date, considerable focus has been on the role of indoleamine 2,3-dioxygenase 1 (IDO1) and its catabolite, kynurenine (Kyn). However, increasing evidence has demonstrated that downstream KP enzymes and their associated metabolite products can also elicit tumor-microenvironment immune suppression. These advancements in our understanding of the tumor promotive role of the KP have led to the conception of novel therapeutic strategies to target the KP pathway for anti-cancer effects and reversal of immune escape. This review aims to 1) highlight the known biological functions of key enzymes in the KP, and 2) provide a comprehensive overview of existing and emerging therapies aimed at targeting discrete enzymes in the KP for anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) secreted by tumors was reported as a deleterious factor that led to the reduction of lymphocyte infiltration and the poorer efficacy of ICIs in vivo. This study aimed to explore whether PCSK9 expression in tumor tissue could predict the response of advanced non-small cell lung cancer (NSCLC) to anti-PD-1 immunotherapy and the synergistic antitumor effect of the combination of the PCSK9 inhibitor with the anti-CD137 agonist. One hundred fifteen advanced NSCLC patients who received anti-PD-1 immunotherapy were retrospectively studied with PCSK9 expression in baseline NSCLC tissues detected by immunohistochemistry (IHC). The mPFS of the PCSK9lo group was significantly longer than that of the PCSK9hi group [8.1 vs. 3.6 months, hazard ratio (HR): 3.450; 95% confidence interval (CI), 2.166-5.496]. A higher objective response rate (ORR) and a higher disease control rate (DCR) were observed in the PCSK9lo group than in the PCSK9hi group (54.4% vs. 34.5%, 94.7% vs. 65.5%). Reduction and marginal distribution of CD8+ T cells were observed in PCSK9hi NSCLC tissues. Tumor growth was retarded by the PCSK9 inhibitor and the anti-CD137 agonist alone in the Lewis lung carcinoma (LLC) mice model and further retarded by the PCSK9 inhibitor in combination with the CD137 agonist with long-term survival of the host mice with noticeable increases of CD8+ and GzmB+ CD8+ T cells and reduction of Tregs. Together, these results suggested that high PCSK9 expression in baseline tumor tissue was a deleterious factor for the efficacy of anti-PD-1 immunotherapy in advanced NSCLC patients. The PCSK9 inhibitor in combination with the anti-CD137 agonist could not only enhance the recruitment of CD8+ and GzmB+ CD8+ T cells but also deplete Tregs, which may be a novel therapeutic strategy for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators in tumor microenvironment (TME) due to their potent immunosuppressive capacity. MDSCs are the products of myeloid progenitor abnormal differentiation in bone marrow, which inhibits the immune response mediated by T cells, natural killer cells and dendritic cells; promotes the generation of regulatory T cells and tumor-associated macrophages; drives the immune escape; and finally leads to tumor progression and metastasis. In this review, we highlight key features of MDSCs biology in TME that are being explored as potential targets for tumor immunotherapy. We discuss the therapies and approaches that aim to reprogram TME from immunosuppressive to immunostimulatory circumstance, which prevents MDSC immunosuppression activity; promotes MDSC differentiation; and impacts MDSC recruitment and abundance in tumor site. We also summarize current advances in the identification of rational combinatorial strategies to improve clinical efficacy and outcomes of cancer patients, via deeply understanding and pursuing the mechanisms and characterization of MDSCs generation and suppression in TME. [ABSTRACT FROM AUTHOR]

Introduction: Osimertinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with EGFR-mutant nonsmall cell lung cancer (NSCLC). However, the emergence of acquired resistance due to the EGFR-Del19/T790M/C797S mutation limits the clinical application of osimertinib. Feiyiliu Mixture (FYLM), a clinical experience formula of Chinese medicine, was used to treat lung cancer with good clinical efficacy. In this study, we aimed to investigate the mechanism by which Feiyiliu Mixture delays osimertinib resistance in EGFR-mutant cell lines and EGFR-mutant cell tumor-bearing mice. Methods: The osimertinib-resistant cell models were established in mouse Lewis lung carcinoma (LLC) cells transfected with EGFR-Del19/T790M/C797S mutant lentivirus. In cell experiments, after 48 h of treatment with Feiyiliu Mixturecontaining serum, MTT assay was used to detect the relative cell viability, and western blotting was used to detect EGFR protein phosphorylation expression. In animal experiments, C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma cells stably expressing EGFR-Del19/T790M/C797S mutations to construct a xenograft model. After 2 weeks of Feiyiliu Mixture and/or osimertinib treatment, the expression of proliferation-related, apoptosis-related and PRC1/Wnt/EGFR pathway markers was detected by real-time qPCR, western blotting and immunohistochemistry. Results: The results showed that when combined with osimertinib, Feiyiliu Mixture synergistically reduces proliferation and increases apoptosis to improve drug resistance. In vitro, Feiyiliu Mixture-containing serum reduced the EGFR phosphorylation. In vivo, Feiyiliu Mixture downregulated the expression of cyclin B1 and Bcl-2 while upregulating the level of cleaved Caspase-3 protein, indicating that FeiyiliuMixture promotes apoptosis. Furthermore, FeiyiliuMixture reduced the expression of p-EGFR, p-Akt, PRC1 and Wnt pathway-related proteins such as ß-catenin, c-Myc and c-Jun. Conclusion: The present study identified that Feiyiliu Mixture inhibited PRC1/Wnt/EGFR pathway activation, reduced proliferation, and promoted apoptosis, thereby increasing the sensitivity of EGFR-mutant non-small cell lung cancer to osimertinib. Our study provided a new idea for Chinese medicine to play a role in enhancing efficacy and reducing toxicity in the treatment of non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

With the major advances in cancer immunology and immunotherapy, it is critical to consider that most immune cells are short-lived and need to be continuously replenished from hematopoietic stem and progenitor cells. Hematologic abnormalities are prevalent in cancer patients, and many ground-breaking studies over the past decade provide insights into their underlying cellular and molecular mechanisms. Such studies demonstrate that the dysfunction of hematopoiesis is more than a side-effect of cancer pathology, but an important systemic feature of cancer disease. Here we review these many advances, covering the cancer-associated phenotypes of hematopoietic stem and progenitor cells, the dysfunction of myelopoiesis and erythropoiesis, the importance of extramedullary hematopoiesis in cancer disease, and the developmental origins of tumor associated macrophages. We address the roles of many secreted mediators, signaling pathways, and transcriptional and epigenetic mechanisms that mediate such hematopoietic dysfunction. Furthermore, we discuss the important contribution of the hematopoietic dysfunction to cancer immunosuppression, the possible avenues for therapeutic intervention, and highlight the unanswered questions and directions for future work. Overall, hematopoietic dysfunction is established as an active component of the cancer disease mechanisms and an important target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Gypenosides (GYP) exerted anticancer activity against various cancers. However, the mechanism of GYP against lung cancer (LC) in vivo remains unclear. This study aims to reveal the potential mechanism of GYP against LC and enhancing cisplatin efficacy using a comprehensive analysis of metabolomics, network analysis. Pharmacodynamic results showed that GYP inhibited tumor growth, reduced tumor volume and tumor weight, and alleviated pathological symptoms in Lewis tumor-bearing mice, and GYP could enhance the anti-LC effects of cisplatin. Using serum metabolomics methods, 53 metabolites were found to be significantly altered in the model group, and the levels of 23 biomarkers were significantly restored after GYP treatment. GYP-related metabolic pathways involved six pathways, including alpha-linolenic acid metabolism, glutathione metabolism, sphingolipid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and primary bile acid biosynthesis. 57 genes associated with differential metabolites of GYP recovery and 7 genes of 11 saponins of GYP against LC were screened by network analysis, the STRING database was used to find the association between 57 genes and 7 genes, and a compound-intersection gene-metabolite related gene-metabolite-pathway network was constructed, and STAT3, MAPK14, EGFR and TYMS might be the crucial targets of GYP against LC. Western blot results showed that GYP restored the levels of STA3, MAPK14, EGFR, and TYMS in the model group, and GYP also restored the levels of STAT3 and MAPK14 in the cisplatin group, indicating that GYP might exert anti-LC effects and enhance the pharmacological effects of cisplatin through MAPK14/STAT3 signaling pathway. Our method revealed the effect and mechanism of GYP on LC and the pharmacological effects of GYPenhanced chemotherapeutic agent cisplatin, which provided some reference for the development of anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Therapeutic tumor vaccines have become an important breakthrough in the treatment of various solid tumors including lung cancer. Dendritic cells (DCs)-based tumor vaccines targeting tumor-associated antigens (TAAs) play a key role in immunotherapy and immunoprevention. However, the weak immunogenicity of TAAs and low immune response rates are a major challenge faced in the application of therapeutic tumor vaccines. Here, we tested whether targeting an attractive target Mesothelin (MSLN) and PD-L1 immune checkpoint molecule to DCs in vivo would elicit therapeutic antitumor cytotoxic T lymphocyte (CTL) response. We generated specific MSLN fragment combined with PD-L1 and GM-CSF peptide immunogen (MSLN-PDL1-GMCSF) based on the novel anti-PD-L1 vaccination strategy we recently developed for the cancer treatment and prevention. We found that DCs loaded with MSLN-PDL1-GMCSF vaccine elicited much stronger endogenous anti-PD-L1 antibody and T cell responses in immunized mice and that antigen specific CTLs had cytolytic activities against tumor cells expressing both MSLN and PD-L1. We demonstrated that vaccination with MSLN-PDL1-GMCSF potently inhibited the tumor growth of MSLN+ and PD-L1+ lung cancer cells, exhibiting a significant therapeutic anti-tumor potential. Furthermore, PD-1 blockade further improved the synergistic antitumor therapeutic efficacy of MSLN-PDL1-GMCSF vaccine in immunized mice. In summary, our data demonstrated for the first time that this PD-L1-containing MSLN therapeutic vaccine can induce persistent anti-PD-L1 antibody and CTL responses, providing an effective immunotherapeutic strategy for lung cancer immunotherapy by combining MSLN-PDL1-GMCSF vaccine and PD-1 blockade. [ABSTRACT FROM AUTHOR]

The combination of immunotherapy with platinum-based chemotherapy has become the first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) with negative driver gene mutations. However, finding an ideal chemotherapeutic regimen for immunotherapy and exploring the underlying mechanism have noticeably attracted clinicians' attention. In this study, we found that cisplatin induced ferroptosis of tumor cells, followed by N1 neutrophil polarization in the tumor microenvironment, which in turn remodeled the "cold" tumor to a "hot" one through enhancing T-cell infiltration and Th1 differentiation. Based on the important role of tumor ferroptosis in the immune-promoting effect of cisplatin, we noticed that the combination of a ferroptosis activator showed a synergistic effect with chemoimmunotherapy of epidermal growth factor receptor (EGFR)-mutant NSCLC, which would be an effective strategy to overcome immunotherapy resistance in NSCLC patients harboring driver mutations. [ABSTRACT FROM AUTHOR]

The combination of immunotherapy with platinum-based chemotherapy has become the first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) with negative driver gene mutations. However, finding an ideal chemotherapeutic regimen for immunotherapy and exploring the underlying mechanism have noticeably attracted clinicians' attention. In this study, we found that cisplatin induced ferroptosis of tumor cells, followed by N1 neutrophil polarization in the tumor microenvironment, which in turn remodeled the "cold" tumor to a "hot" one through enhancing T-cell infiltration and Th1 differentiation. Based on the important role of tumor ferroptosis in the immune-promoting effect of cisplatin, we noticed that the combination of a ferroptosis activator showed a synergistic effect with chemoimmunotherapy of epidermal growth factor receptor (EGFR)-mutant NSCLC, which would be an effective strategy to overcome immunotherapy resistance in NSCLC patients harboring driver mutations. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4/GPR48), a member of the GPCR (G protein-coupled receptors) superfamily, subfamily B, is a common intestinal crypt stem cell marker. It binds R-spondins/Norrin as classical ligands and plays a crucial role in Wnt signaling potentiation. Interaction between LGR4 and R-spondins initiates many Wnt-driven developmental processes, e.g., kidney, eye, or reproductive tract formation, as well as intestinal crypt (Paneth) stem cell pool maintenance. Besides the well-described role of LGR4 in development, several novel functions of this receptor have recently been discovered. In this context, LGR4 was indicated to participate in TGFβ and NFκB signaling regulation in hematopoietic precursors and intestinal cells, respectively, and found to be a new, alternative receptor for RANKL (Receptor Activator of NF kappa B Ligand) in bone cells. LGR4 inhibits the process of osteoclast differentiation, by antagonizing the interaction between RANK (Receptor Activator of NF kappa B) and its ligand-RANKL. It is also known to trigger anti-inflammatory responses in different tissues (liver, intestine, cardiac cells, and skin), serve as a sensor of the circadian clock in the liver, regulate adipogenesis and energy expenditure in adipose tissue and skeletal muscles, respectively. The extracellular domain of LGR4 (LGR4-ECD) has emerged as a potential new therapeutic for osteoporosis and cancer. LGR4 integrates different signaling pathways and regulates various cellular processes vital for maintaining whole-body homeostasis. Yet, the role of LGR4 in many cell types (e.g. pancreatic beta cells) and diseases (e.g., diabetes) remains to be elucidated. Considering the broad spectrum of LGR4 actions, this review aims to discuss both canonical and novel roles of LGR4, with emphasis on emerging research directions focused on this receptor. [ABSTRACT FROM AUTHOR]

As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists. [ABSTRACT FROM AUTHOR]

Background: Malignant tumors accompanied with malignant pleural effusion (MPE) often indicate poor prognosis. The therapeutic effect and mechanism of intrapleural injection of anti-programmed cell death protein 1 (PD1) on MPE need to be explored. Methods: A preclinical MPE mouse model and a small clinical study were used to evaluate the effect of intrapleural injection of anti-PD1 antibody. The role of immune cells was observed via flow cytometry, RNA-sequencing, quantitative PCR, western blot, immunohistochemistry, and other experimental methods. Results: Intrathoracic injection of anti-PD1 monoclonal antibody (mAb) has significantly prolonged the survival time of mice (P = 0.0098) and reduced the amount of effusion (P = 0.003) and the number of cancer nodules (P = 0.0043). Local CD8+ T cells participated in intrapleural administration of anti-PD1 mAb. The proportion of CD69+, IFN-γ+, and granzyme B+ CD8+ T cells in the pleural cavity was increased, and the expression of TNF-α and IL-1β in MPE also developed significantly after injection. Local injection promoted activation of the CCL20/CCR6 pathway in the tumor microenvironment and further elevated the expression of several molecules related to lymphocyte activation. Clinically, the control rate of intrathoracic injection of sintilimab (a human anti-PD1 mAb) for 10 weeks in NSCLC patients with MPE was 66.7%. Local injection improved the activity and function of patients' local cytotoxic T cells (CTLs). Conclusions: Intrapleural injection of anti-PD1 mAb could control malignant pleural effusion and the growth of cancer, which may be achieved by enhancing local CTL activity and cytotoxicity. [ABSTRACT FROM AUTHOR]

Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia–reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders. [ABSTRACT FROM AUTHOR]

Tumor-associated angiogenesis is a key target for anti-cancer therapy. The imbalance between pro-angiogenic and anti-angiogenic signals elicited by tumor cells or tumor microenvironment always results in activating "angiogenic switch". Tumor angiogenesis functions in multi-aspects of tumor biology, including endothelial cell apoptosis, tumor metastasis, and cancer stem cell proliferation. Numerous studies have indicated the important roles of inexpensive and less toxic natural products in targeting tumor angiogenesis-associated cytokines and apoptotic signaling pathways. Our current knowledge of tumor angiogenesis is based mainly on experiments performed on cells and animals, so we summarized the well-established models for angiogenesis both in vitro and in vivo. In this review, we classified and summarized the anti-angiogenic natural agents (Polyphenols, Polysaccharides, Alkaloids, Terpenoids, Saponins) in targeting various tumor types according to their chemical structures at present, and discussed the mechanistic principles of these natural products on regulating angiogenesis-associated cytokines and apoptotic signaling pathways. This review is to help understanding the recent progress of natural product research for drug development on anti-tumor angiogenesis. [ABSTRACT FROM AUTHOR]

The past two decades witnessed a revolution in our understanding of host–microbiota interactions that led to the concept of the super-organism consisting of a eukaryotic part and a prokaryotic part. Owing to the critical role of gut microbiota in modulating the host immune system, it is not beyond all expectations that more and more evidence indicated that the shift of gut microbiota influenced responses to numerous forms of cancer immunotherapy. Therapy targeting gut microbiota is becoming a promising strategy to improve cancer immunotherapy. In this review, we discuss the role of the gut microbiota in response to cancer immunotherapy, the mechanisms that the gut microbiota influences cancer immunotherapy, and therapeutic strategies targeting gut microbiota to improve cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy is an effective treatment used in multiple tumor treatments, but produces severe side effects including neurotoxicity, anemia, and immunosuppression, which limits its anti-tumor efficacy and increases the risk of infections. Electroacupuncture (EA) is often used to ameliorate these side effects, but its mechanism is unknown. Here, we report that EA on ST36 and SP6 prevents cisplatin-induced neurotoxicity and immunosuppression. EA induces neuroprotection, prevents pain-related neurotoxicity, preserves bone marrow (BM) hematopoiesis, and peripheral levels of leukocytes. EA activates sympathetic BM terminals to release pituitary adenylate cyclase activating polypeptide (PACAP). PACAP-receptor PAC1-antagonists abrogate the effects of EA, whereas PAC1-agonists mimic EA, prevent neurotoxicity, immunosuppression, and preserve BM hematopoiesis during cisplatin chemotherapy. Our results indicate that PAC1-agonists may provide therapeutic advantages during chemotherapy to treat patients with advanced neurotoxicity or neuropathies limiting EA efficacy. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes. [ABSTRACT FROM AUTHOR]

Background: Tumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized. Methods: We employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1α-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice. Results: HBO suppressed hypoxia-induced HIF-1α expression and downstream HIF-1α signaling in NSCLC cells. One HIF-1α-induced glucose metabolism gene—Phosphofructokinase, Platelet (PFKP)—most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1α downregulation. HBO's suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1α/PFKP axis. In vivo , HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner. Conclusions: HBO's repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1α downregulation. HIF-1α's target gene PFKP functions as a central mediator of HBO's effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors. [ABSTRACT FROM AUTHOR]

In a previous study, we have demonstrated that p62, a selective receptor of autophagy, can regulate allergic inflammation. In the present study, microRNA array analysis showed that miR-154-5p was increased by antigen (DNP-HSA) in a p62-dependent manner in rat basophilic leukemia cells (RBL2H3). NF-kB directly increased the expression of miR-154-5p. miR-154-5p mediated in vivo allergic reactions, including passive cutaneous anaphylaxis and passive systemic anaphylaxis. Cytokine array analysis showed that antigen stimulation increased the expression of MCP1 in RBL2H3 cells in an miR-154-5p-dependent manner. Reactive oxygen species (ROS)-ERK-NF-kB signaling increased the expression of MCP1 in antigen-stimulated RBL2H3 cells. Recombinant MCP1 protein induced molecular features of allergic reactions both in vitro and in vivo. Anaphylaxis-promoted tumorigenic potential has been known to be accompanied by cellular interactions involving mast cells, and macrophages, and cancer cells. Our experiments employing culture medium, co-cultures, and recombinant MCP1 protein showed that miR-154 and MCP1 mediated these cellular interactions. MiR-154-5p and MCP1 were found to be present in exosomes of RBL2H3 cells. Exosomes from PSA-activated BALB/C mouse induced molecular features of passive cutaneous anaphylaxis in an miR-154-5p-dependent manner. Exosomes from antigen-stimulated RBL2H3 cells enhanced both tumorigenic and metastatic potentials of B16F1 melanoma cells in an miR-154-5p-dependent manner. Exosomes regulated both ROS level and ROS mediated cellular interactions during allergic inflammation. Our results indicate that the miR-154-5p-MCP1 axis might serve as a valuable target for the development of anti-allergy therapeutics. [ABSTRACT FROM AUTHOR]

Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators. [ABSTRACT FROM AUTHOR]

The ongoing loss of skeletal muscle is a central event of cancer cachexia, and its consequences include adverse effects on patient's quality of life and survival. Alpinetin (Alp), a natural plant-derived flavonoid obtained from Alpinia katsumadai Hayata, has been reported to possess potent anti-inflammatory and antitumor activities. This study aimed to explore the therapeutic effect and underlying mechanism of Alp in the prevention of cancer cachexia. We found that Alp (25–100 μM) dose-dependently attenuated Lewis lung carcinoma–conditioned medium-induced C2C12 myotube atrophy and reduced expression of the E3 ligases Atrogin-1 and MuRF1. Moreover, Alp administration markedly improved vital features of cancer cachexia in vivo with visible reduction of the loss of tumor-free body weight and wasting of multiple tissues, including skeletal muscle, epididymal fat, and decreased expression of Atrogin-1 and MuRF1 in cachectic muscle. Alp suppressed the elevated spleen weight and serum concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Further, Alp treatment remained protective against cancer cachexia in the advanced stage of tumor growth. Molecular docking results suggested that Alp was docked into the active site of PPARγ with the docking score of –7.6 kcal/mol, forming a hydrogen bond interaction with PPARγ protein amino acid residue HIS449 with a bond length of 3.3 Å. Mechanism analysis revealed that Alp activated PPARγ, resulting in the downregulated phosphorylation of NF-κB and STAT3 in vitro and in vivo. PPARγ inhibition induced by GW9662 notably attenuated the improvement of Alp on the above cachexia phenomenon, indicating that PPARγ activation mediated the therapeutic effect of Alp. These findings suggested that Alp might be a potential therapeutic candidate against cancer cachexia. [ABSTRACT FROM AUTHOR]

The accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles to achieve an appropriate anti-tumor immune response and successful tumor immunotherapy. MDSCs in tumor-bearing hosts are primarily polymorphonuclear (PMN-MDSCs). However, the mechanisms regulating the development of MDSCs remain poorly understood. In this report, we showed that interferon regulatory factor 4 (IRF4) plays a key role in the development of PMN-MDSCs, but not monocytic MDSCs. IRF4 deficiency caused a significant elevation of PMN-MDSCs and enhanced the suppressive activity of PMN-MDSCs, increasing tumor growth and metastasis in mice. Mechanistic studies showed that c-Myc was up-regulated by the IRF4 protein. Over-expression of c-Myc almost abrogated the effects of IRF4 deletion on PMN-MDSCs development. Importantly, the IRF4 expression level was negatively correlated with the PMN-MDSCs frequency and tumor development but positively correlated with c-Myc expression in clinical cancer patients. In summary, this study demonstrated that IRF4 represents a novel regulator of PMN-MDSCs development in cancer, which may have predictive value for tumor progression. [ABSTRACT FROM AUTHOR]

Cachexia is a multifactorial inflammatory syndrome with high prevalence in cancer patients. It is characterized by a metabolic chaos culminating in drastic reduction in body weight, mainly due to skeletal muscle and fat depletion. Currently, there is not a standard intervention for cachexia, but it is believed that a dynamic approach should be applied early in the course of the disease to maintain or slow the loss of physical function. The present review sought to explain the different clinical and experimental applications of different models of exercise and their contribution to a better prognosis of the disease. Here the advances in knowledge about the application of physical training in experimental models are elucidated, tests that contribute substantially to elucidate the cellular and biochemical mechanisms of exercise in different ways, as well as clinical trials that present not only the impacts of exercise in front cachexia but also the challenges of its application in clinical practice. [ABSTRACT FROM AUTHOR]

Understanding and targeting Notch signaling effectively has long been valued in the field of cancer and other immune disorders. Here, we discuss key discoveries at the intersection of Notch signaling, cancer and immunology. While there is a plethora of Notch targeting agents tested in vitro , in vivo and in clinic, undesirable off-target effects and therapy-related toxicities have been significant obstacles. We make a case for the clinical application of ligand-derived and affinity modifying compounds as novel therapeutic agents and discuss major research findings with an emphasis on Notch ligand-specific modulation of immune responses. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy induces sarcopenia, which is a rapid loss of muscle mass that directly restricts daily activities and leads to poor quality of life and increased mortality. Although hormone-related therapies have been used to improve appetite and nutritional status, current treatments are considered palliative. Thus, the protection of skeletal muscle loss without adverse effects is essential to allow the maintenance of chemotherapy in cancer patients. Magnolol from Magnolia officinalis has several pharmacological effects including anti-cancer and anti-inflammatory activities, but the protection from muscle atrophy is not well-understood. In the present study, we investigated the effects of magnolol on muscle wasting and macrophage subtypes in a cisplatin-induced sarcopenia mouse model. We showed that magnolol significantly attenuated the body weight and the muscle loss induced by cisplatin injection. The diameter of the tibialis anterior muscle was markedly increased after magnolol treatment in cisplatin-treated mice. Importantly, magnolol increased macrophage infiltration into skeletal muscle while not affecting proliferation of macrophages. Magnolol attenuated the imbalance of M1/M2c macrophages by increasing CD206+CD163+ M2c tissue reparative macrophages. Further, magnolol increased insulin-like growth factor (IGF)-1 expression. This effect was also observed in bone marrow-derived macrophages upon magnolol treatment. Taken together, magnolol may be a promising chemoprotective agent for the prevention of muscle atrophy through the upregulating M2c macrophages, which are a major source of IGF-1. [ABSTRACT FROM AUTHOR]

Tumor immunosuppression may assist the immune escape of cancer cells, which promotes tumor metastasis and resistance to chemo-radiotherapy. The therapeutic strategies against tumor immunosuppression mainly focus on blocking immune checkpoint receptors, enhancing T-cell recognition and neutralizing inhibitory molecules. Although immunotherapies based on these strategies have improved the clinical outcomes, immunological nonresponse and resistance are two barriers to tumor eradication. Therefore, there is an urgent need to identify new biomarkers for patient selection and therapeutic targets for the development of combination regimen with immunotherapy. Recent studies have reported that non-protein-coding modulators exhibit important functions in post-transcriptional gene regulation, which subsequently modulates multiple pathophysiological processes, including neoplastic transformation. Differentiated from microRNAs, long non-coding RNAs (lncRNAs) are reported to be involved in various processes of the immune response in the tumor microenvironment (TME) to promote tumor immunosuppression. Currently, studies on tumor immunity regulated by lncRNAs are mainly confined to certain types of cancer cells or stromal cells. Additionally, the majority of studies are focused on the events involved in T cells and myeloid-derived suppressor cells (MDSCs). Although the reported studies have indicated the significance of lncRNAs in immunotherapy, the lack of comprehensive studies prevents us from exploring useful lncRNAs. In the current review, we have summarized the roles of lncRNAs in tumor immune response, and highlighted major lncRNAs as potential biomarkers or therapeutic targets for clinical application of immunotherapy. [ABSTRACT FROM AUTHOR]

Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor adaptive immune response as they recognize antigens presented on MHC class I (MHC-I) molecules usually expressed in all cells and thus also in tumors. However, attempts to translate in clinics vaccination protocols based only on tumor-specific MHC-I-bound peptides have resulted in very limited, if any, success. We believe failure was mostly due to inadequate triggering of the TH arm of adaptive immunity, as TH cells are necessary to trigger and maintain the proliferation of all the immune effector cells required to eliminate tumor cells. In this review, we focus on a novel strategy of anti-tumor vaccination established in our laboratory and based on the persistent expression of MHC class II (MHC-II) molecules in tumor cells. MHC-II are the restricting elements of TH recognition. They are usually not expressed in solid tumors. By genetically modifying tumor cells of distinct histological origin with the MHC-II transactivator CIITA, the physiological controller of MHC-II gene expression discovered in our laboratory, stable expression of all MHC class II genes was obtained. This resulted in tumor rejection or strong retardation of tumor growth in vivo in mice, mediated primarily by tumor-specific TH cells as assessed by both depletion and adoptive cell transfer experiments. Importantly these findings led us to apply this methodology to human settings for the purification of MHC-II-bound tumor specific peptides directly from tumor cells, specifically from hepatocarcinomas, and the construction of a multi-peptide (MHC-II and MHC-I specific) immunotherapeutic vaccine. Additionally, our approach unveiled a noticeable exception to the dogma that dendritic cells are the sole professional antigen presenting cells (APC) capable to prime naïve TH cells, because CIITA-dependent MHC-II expressing tumor cells could also perform this function. Thus, our approach has served not only to select the most appropriate tumor specific peptides to activate the key lymphocytes triggering the anti-tumor effector functions but also to increase our knowledge of intimate mechanisms governing basic immunological processes. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming of lipid metabolism is a hallmark of cancer. Consumption of a high-fat obesogenic diet enhances spontaneous metastasis using a Lewis lung carcinoma (LLC) model. In order to gain further insights into the mechanisms by which dietary fats impact cancer progression, we conducted a lipidomic analysis of primary tumors originated from LLC from mice fed with a standard AIN93G diet or a soybean oil-based high-fat diet (HFD). Hierarchical clustering heatmap analysis of phosphatidylcholine (PC) lipids and phosphatidylethanolamine (PE) lipids demonstrated an increase in polyunsaturated fatty acids (PUFA)-containing phospholipids and a decrease in monounsaturated fatty acids (MUFA)-containing lipids in tumors from mice fed the HFD. The quantities of 51 PC and 24 PE lipids differed in primary tumors of LLC from mice fed the control diet and the HFD. Analysis of triacylglycerol (TAG) lipids identified differences in 32 TAG (by brutto structure) between the two groups; TAG analysis by neutral loss identified 46 PUFA-containing TAG species that were higher in mice fed with the HFD than in the controls. Intake of the HFD did not alter the expression of the de novo lipogenesis enzymes (fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase-1). Our results demonstrate that the dietary fatty acid composition of the HFD is reflected in the higher order lipidomic composition of primary tumors. Subsequent studies are needed to investigate how these lipidomic changes may be used for targeted dietary intervention to reduce tumor growth and malignant progression. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) often expand during cancer or chronic inflammation and dampen immune responses. However, mechanisms underlying their capacity to escape intrinsic apoptosis in the inflammatory environment are still largely unknown. In this study, we investigated this in mouse tumor models with MDSC accumulation. Spontaneous rejection of tumors implanted into mice deficient for the small Ca2+-binding protein S100A4 (S100A4-/-) was accompanied by low numbers of peripheral MDSCs. This was independent of S100A4 expression on tumor cells. In contrast, MDSCs from S100A4-/- tumor-bearing mice showed a diminished resistance to the induction of intrinsic apoptosis. Further studies demonstrated that S100A4 protects MDSCs from apoptosis through toll-like receptor-4/extracellular signal-regulated kinase-dependent caspase-9 inhibition. The finding that S100A4 is critical for MDSC survival in inflammatory environments might have important implications for the clinical treatment of cancer or inflammation-related diseases. [ABSTRACT FROM AUTHOR]

Cytokine gene delivery by viral vectors is a promising novel strategy for cancer immunotherapy. Semliki Forest virus (SFV) has many advantages as a delivery vector, including the ability to (i) induce p53-independent killing of tumor cells via apoptosis, (ii) elicit a type-I interferon (IFN) response, and (iii) express high levels of the transgene. SFV vectors encoding cytokines such as interleukin (IL)-12 have shown promising therapeutic responses in experimental tumor models. Here, we developed two new recombinant SFV vectors encoding either murine tumor necrosis factor-α (TNF-α) or murine interferon-γ (IFN-γ), two cytokines with documented immunostimulatory and antitumor activity. The SFV vector showed high infection rate and cytotoxicity in mouse and human lung carcinoma cells in vitro. By contrast, mouse and human macrophages were resistant to infection with SFV. The recombinant SFV vectors directly inhibited mouse lung carcinoma cell growth in vitro, while exploiting the cancer cells for production of SFV vector-encoded cytokines. The functionality of SFV vector-derived TNF-α was confirmed through successful induction of cell death in TNF-α-sensitive fibroblasts in a concentration-dependent manner. SFV vector-derived IFN-γ activated macrophages toward a tumoricidal phenotype leading to suppressed Lewis lung carcinoma cell growth in vitro in a concentration-dependent manner. The ability of SFV to provide functional cytokines and infect tumor cells but not macrophages suggests that SFV may be very useful for cancer immunotherapy employing tumor-infiltrating macrophages. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an in vitro growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC) and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO) and cytokines by activated macrophages was quantified. We found that IFN-γ alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-γ was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70). Furthermore, IFN-γ was shown to suppress macrophage IL-10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-γ and TLR agonists may offer new avenues for macrophage-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on. [ABSTRACT FROM AUTHOR]