Mechanism and effects of extramedullary hematopoiesis on anti-tumor immunity

Cancer immunotherapy is a preferred strategy for boosting anti-tumor immunity to eliminate malignant cells and is considered a major breakthrough in the field of cancer treatment however,immunosuppressive cells in the tumor microenvironment(TME)pose a major obstacle to the efficacy of immunotherapy.Myeloid cells,such as tumor-a ssociated macrophages(TAMs)and myeloid-derived suppressor cells(MDSCs).

The effects of irreversible electroporation triggering anti-tumor immunity and the value of its combination with immunotherapy

Recently,interventional ablation techniques have gained prominence in tumor treatment guidelines and complement traditional approaches,such as surgery,chemotherapy,and radiotherapy.Conventional ablation techniques,such as microwave,radiofrequency,and cryoablation,have been used;however,they have certain limitations,including the risk of damaging surrounding normal tissues and the heat sink effect caused by tumor blood flow.1 Irreversible electroporation(IRE),an ablation technology independent of thermal energy,is a promising alternative.2 Clinical studies have demonstrated IRE's efficacy in treating tumors,such as pancreatic and liver tumors.3 Recent research has shown that IRE can elicit specific anti-tumor immune responses in the body.5 IRE also plays a crucial role in eliminating residual tumor cells postoperatively and preventing tumor recurrence.

Radiofrequency ablation,heat shock protein 70 and potential anti-tumor immunity in hepatic and pancreatic cancers:a minireview

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive surgical procedure which has widespread popularity in the treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA stimulates anti-tumor immunity, possibly through the induction heat shock protein 70 (HSP70) expression. HSP70 has the capacity to affect the immunogenicity of tumor cells, to chaperone antigenic peptides and deliver these into antigen presentation pathways within antigen-presenting cells, and to activate and regulate innate and adaptive immunity, which makes it useful in immunotherapeutic strategies for the treatment of cancers. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1991-2010) on anti-tumor immunity, heat shock protein 70, radiofrequency ablation, hepatic cancer, pancreatic cancer, and other related subjects. RESULTS: RFA has an increasing application in the surgical treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA can induce the expression of HSP70 which possesses properties that enable it to influence a variety of immunological processes. Tumor-derived HSP70 is regarded as a potent adjuvant facilitating presentation of tumor antigens and induction of anti-tumor immunity. CONCLUSIONS: This review addresses the potential association of RFA, HSP70, and anti-tumor immunity in treatment of hepatic and pancreatic cancers. To establish direct evidence of a potential association of RFA, HSP70, and anti-tumor immunity in hepatic and pancreatic cancers, further investigations should be conducted.

Anti-tumor Immunity Elicited by Adenovirus Encoding AdhTrp2 or AdmTrp2 without Vitiligo

To compare the difference in tumor immunity and autoimmunity elicited by adenovirus （Ad） encoding human or murine tyrosinase-related protein 2 （AdhTRP2 or AdmTRP2）, and to find the most effective way to induce immunity by AdhTRP2 or AdmTRP2, C57BL/6 mice were immunized with AdhTRP2 or AdmTRP2 intramuscularly at different doses of 10^5, 10^6, 10^7 and 10^8 separately （ 10 mice for each dose）. Two weeks after the immunization, in vivo CTL assay and intracellular staining （ICS） of IFN-γ were carried out to analyze the dose-effect relationship. Tumor growth and vitiligo （as an sign of autoimmunity） were observed until 3 months after challenge with 10^5 B 16F10 tumor cells. The results showed that Ad encoding AdmTrp2 induced weak tumor immune response. Similar immunization with AdhTrp-2 elicited stronger protective immunity. CTL activity and IFN-γ-produced CD8＋T cells were directly proportional to dose of AdhTrp2 or AdmTrp2. Moreover, AdhTrp2 group showed tumor rejection in 100% of challenged mice till the end of 3rd month while 60% of mice immunized with AdmTrp2 were protected against tumor. In the whole process of this experiment, no vitiligo was observed in mice immunized either with AdhTrp2 or AdmTrp2. It is concluded that anti-melanoma responses induced by genetic vaccination expressing xenoantigens breaks immune tolerance effectively and is able to elicit strong antigen-specific cytotoxic T cell response without vitiligo.

Effect of nutritional support + intravenous chemotherapy on anti-tumor immunity and cancer cell proliferation in patients with colon cancer complicated by incomplete intestinal obstruction

Objective:To study the effect of nutritional support + intravenous chemotherapy on anti-tumor immunity and cancer cell proliferation in patients with colon cancer complicated by incomplete intestinal obstruction.Methods: Patients with colon cancer complicated by incomplete intestinal obstruction who were treated in Midi Branch, Pangang Group General Hospital between March 2015 and October 2017 were selected and randomly divided into the nutrition group who accepted nutritional support + FOLFOX4 intravenous chemotherapy and the control group who accepted FOLFOX4 intravenous chemotherapy alone, and they underwent surgery after two cycles of chemotherapy. The contents of immune cells in peripheral blood and the contents of immune cytokines in serum were determined before chemotherapy and two cycles after chemotherapy;the expression levels of proliferation genes in colon cancer lesions were determined after surgical resection.Results:Compared with those of same group before chemotherapy, peripheral blood Treg, Th9, Th17 and Th22 contents as well as serum IL-4, IL-9, IL-10, TGF-β1, IL-17 and IL-22 contents of nutrition group were decreased significantly after chemotherapywhereas peripheral blood Treg, Th9, Th17 and Th22 contents as well as serum IL-4, IL-9, IL-10, TGF-β1, IL-17 and IL-22 contents of control group did not change significantly after chemotherapy, and compared with those after chemotherapy between groups, peripheral blood Treg, Th9, Th17 and Th22 contents as well as serum IL-4, IL-9, IL-10, TGF-β1, IL-17 and IL-22 contents of nutrition group were significantly lower than those of control group, and CyclinD1, Bcl-2, USP22, VEGF and N-cadherin mRNA expression were not different from those of control group.Conclusion:Nutritional support + intravenous chemotherapy can improve the anti-tumor immune response without affecting the proliferation of cancer cells in the lesion of patients with colon cancer complicated by incomplete intestinal obstruction.

Anti-tumor immunity,autophagy and chemotherapy

Autophagy or self-digestion of cells is activated upon various stressful stimuli and has been found to be a survival and drug resistance pathway in cancer.However,genetic studies support that autophagy can act as a tumor suppressor.Furthermore,defective autophagy is implicated in tumorigenesis,as well.The precise impact of autophagy on malignant transformation has not yet been clarified,but recent data suggest that this complex process is mainly directed by cell types,phases,genetic background and microenvironment.Relation of autophagy to anticancer immune responses may indicate a novel aspect in cancer chemotherapy.

Wilfoside C3N Promotes Tumor Cell Death by Activating Gammadelta T Cells-Mediated Anti-tumor Immunity

Vδ1^+γδ T lymphocytes are known to play important roles in anti-tumor immunity.We recently reported an anti-tumor activity of wilfoside C3 N,an active component extracted from Chinese medicinal herbs.In the current study,we evaluated the role of Vδ1^+γδ T cells in C3 N anti-tumor activity using an in vitro cell co-culture model.We found that C3 N induced the ECA109 tumor cells to undergo apoptosis in the presence of Vδ1^+γδ T cells.The level of ECA109 apoptosis maximized when both C3 N and Vδ1 + γδ T cells were present,which correlated with the increased expression of Fas on ECA109 and Fas ligand on Vδ1^+γδ T cells induced by C3 N.In addition,C3 N also enhanced secretion of cytokines,perforin and granzymes by Vδ1^+γδ T cells.These observations suggest that activation of Vδ1^+ γδ T cells may play a critical role in C3N-mediated anti-tumor activity.

Effects and possible anti-tumor immunity of electrochemotherapy with bleomycin on human colon cancer xenografts in nude mice

AIM: To evaluate the anti-tumor effects and possible involvement of anti-tumor immunity of electrochemotherapy (ECT) employing electroporation and bleomycin in human colon cancer xenografts in nude mice, and to establish the experimental basis for clinical application of ECT.METHODS: Forty nude mice, inoculated subcutaneously human colon cancer cell line LoVo for 3 wk, were allocated randomly into four groups: B+E+ (ECT), B+E- (administration of bleomycin alone), B-E+ (administration of electric pulses alone), and B-E- (no treatment). Tumor volumes were measured daily. The animals were killed on the 7th d, the weights of xenografts were measured, and histologies of tumors were evaluated. Cytotoxicity of spleen natural killer (NK) and lymphokine-activated killer (LAK) cells was then assessed by lactic dehydrogenase release assay.RESULTS: The mean tumor volume of group B+E+ was statistically different from the other three groups after the treatment (F= 36.80, P＜0.01). There was one case of complete response, seven cases of partial response (PR) in group B+E+, one case of PR in group B+E- and group B-E+ respectively, and no response was observed in group B-E-. The difference of response between group B+E+ and the other three groups was statistically significant (χ2 = 25.67, P＜0.01). Histologically, extensive necrosis of tumor cells with considerable vascular damage and inflammatory cells infiltration were observed in group B+E+. There was no statistical difference between the cytotoxicity of NK and LAK cells in the four treatment groups.CONCLUSION: ECT significantly enhances the chemosensitivity and effects of chemotherapy in human colon cancer xenografts in nude mice, and could be a kind of novel treatment modality for human colon cancer.The generation of T-cell-dependent, tumor-specific immunity might be involved in the process of ECT.

Methyltransferase-like 3(METTL3)inhibition potentiates anti-tumor immunity:a novel strategy for improving anti-PD1 therapy

In a recent article published in Cancer Discovery,Guirguis et al.demonstrated that enzymatic inhibitors of the m6 A methyltransferase METTL3 induced a formation of immunostimulatory doublestranded mRNAs(dsRNAs)in cancer cells,which triggered a profound tumor-cell-intrinsic interferon response leading to an enhanced antigen presentation and thereby increased killing of tumor cells by cytotoxic CD8+T-lymphocytes.The inhibition of METTL3 synergized with anti-PD1 immunotherapy,highlighting its potential for improving cancer treatment.

Herb pair of Huangqi-Danggui exerts anti-tumor immunity to breast cancer by upregulating PIK3R1

Background:According to traditional Chinese medicine(TCM),drugs supplementing the vital energy,Qi,can eliminate tumors by restoring host immunity.The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs,specifically the paired use of Huangqi and Danggui.Methods:Analysis of compatibility regularity was conducted to screen the combination of Qi-supplementing TCMs.Using the MTT assay and a transplanted tumor mice model,the anti-tumor effects of combination TCMs were investigated in vitro and in vivo.High content analysis and flow cytometry were then used to evaluate cellular immunity,followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms.Finally,the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments.Results:There is an optimal combination of Huangqi and Danggui that,administered as an aqueous extract,can activate immunity to suppress tumor and is more effective than each drug on its own in vitro and in vivo.Based on network pharmacology analysis,PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui.Molecular docking analysis shows 6 components of the combined Danggui and Huangqi extract(quercetin,jaranol,isorhamnetin,kaempferol,calycosin,and suchilactone)that bind to PIK3R1.Jaranol is the most important component against breast cancer.The suchilactone/jaranol combination and,especially,the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract.Conclusions:The combination of Huangqi and Danggui can activate immunity to suppress breast cancer and is more effective than the individual drugs alone.

Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma(PAAD)patients.Proper regulation could improve survival.Melatonin is an endogenous hormone that delivers multiple bioactivities.Here we showed that pancreatic melatonin level is associated with patients'survival.In PAAD mice models,melatonin supplementation suppressed tumor growth,while blockade of melatonin pathway exacerbated tumor progression.This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils(TANs),and TANs depletion reversed effects of melatonin.Melatonin induced TANs infiltration and activation,therefore induced cell apoptosis of PAAD cells.Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells.Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation.Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype,with increased neutrophil extracellular traps(NETs)causing tumor cell apoptosis through cell-to-cell contact.Proteomics analysis revealed that this reactive oxygen species(ROS)-mediated inhibition was fueled by fatty acid oxidation(FAO)in neutrophils,while FAO inhibitor abolished the anti-tumor effect.Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration.CXCL2,or TANs,combined with NET marker,can better predict patients'prognosis.Collectively,we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.

The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment:molecular mechanisms and therapeutic controversy

The advent of immunotherapy has significantly reshaped the landscape of cancer treatment,greatly enhancing therapeutic outcomes for multiple types of cancer.However,only a small subset of individuals respond to it,underscoring the urgent need for new methods to improve its response rate.Ferroptosis,a recently discovered form of programmed cell death,has emerged as a promising approach for anti-tumor therapy,with targeting ferroptosis to kill tumors seen as a potentially effective strategy.Numerous studies suggest that inducing ferroptosis can synergistically enhance the effects of immunotherapy,paving the way for a promising combined treatment method in the future.Nevertheless,recent research has raised concerns about the potential negative impacts on anti-tumor immunity as a consequence of inducing ferroptosis,leading to conflicting views within the scientific community about the interplay between ferroptosis and anti-tumor immunity,thereby underscoring the necessity of a comprehensive review of the existing literature on this relationship.Previous reviews on ferroptosis have touched on related content,many focusing primarily on the promoting role of ferroptosis on anti-tumor immunity while overlooking recent evidence on the inhibitory effects of ferroptosis on immunity.Others have concentrated solely on discussing related content either from the perspective of cancer cells and ferroptosis or from immune cells and ferroptosis.Given that both cancer cells and immune cells exist in the tumor microenvironment,a one-sided discussion cannot comprehensively summarize this topic.Therefore,from the perspectives of both tumor cells and tumor-infiltrating immune cells,we systematically summarize the current conflicting views on the interplay between ferroptosis and anti-tumor immunity,intending to provide potential explanations and identify the work needed to establish a translational basis for combined ferroptosis-targeted therapy and immunotherapy in treating tumors.

Impact of exercise on markers of B cell-related immunity:A systematic review

Background:B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins.Exercise alters B cell counts and immunoglobulin levels,but evidence-based conclusions on potential benefits for adaptive immunity are lacking.This systematic review assessed current literatures on the impact of acute exercise and exercise training on B cells,immunoglobulins,and markers of secretory immunity in human biofluids.Methods:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,MEDLINE,Web of Science,and Embase were searched on March 8,2023.Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions,immunoglobulin levels,salivary flow rate,or secretory immunoglobulin A secretion rate were included.Quality and reporting of exercise training studies were assessed using the Tool for the Assessment of Study Quality and reporting in Exercise.Study characteristics,outcome measures,and statistically significant changes were summarized tabularly.Results:Of the 67 eligible studies,22 applied acute exercise and 45 applied exercise training.All included outcomes revealed significant alterations over time in acute exercise and exercise training context,but only a few investigations showed significant differences compared to control conditions.Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training.Conclusion:B cell-related outcomes are altered by acute exercise and exercise training,but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities.Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

The role of innate immunity in diabetic nephropathy and their therapeutic consequences

Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

The Magnaporthe oryzae effector Avr-PikD suppresses rice immunity by inhibiting an LSD1-like transcriptional activator

Avirulence effectors(Avrs),encoded by plant pathogens,can be recognized by plants harboring the corresponding resistance proteins,thereby initiating effector-triggered immunity(ETI).In susceptible plants,however,Avrs can function as effectors,facilitating infection via effector-triggered susceptibility(ETS).Mechanisms of Avr-mediated ETS remain largely unexplored.Here we report that the Magnaporthe oryzae effector Avr-PikD enters rice cells via the canonical cytoplasmic secretion pathway and suppresses rice basal defense.Avr-PikD interacts with an LSD1-like transcriptional activator AKIP30 of rice,and AKIP30 is also a positive regulator of rice immunity,whereas Avr-PikD impedes its nuclear localization and suppresses its transcriptional activity.In summary,M.oryzae delivers Avr-PikD into rice cells to facilitate ETS by inhibiting AKIP30-mediated transcriptional regulation of immune response against M.oryzae.