DNA Damage-driven Inflammatory Cytokines:Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy

DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

SR-BI expression regulates the gastric cancer tumor immune microenvironment and is associated with poor prognosis

Aim:Scavenger receptor class B,type I(SR-BI)is an integral plasma membrane protein that has been reported to be overexpressed in various malignancies,such as renal cancer,breast cancer,and prostate cancer,and is an independent prognostic factor.However,the clinical value and expression of SR-BI in GC are unknown.Our research aimed to explore the role of SR-BI in combination with immune markers as a diagnostic and prognostic marker for gastric cancer(GC).Methods:GC tissues,paracancerous tissues,and clinicopathological data of 149 patients were collected.The expression level of SR-BI,Tumor-infiltrating lymphocytes(TILs),and PD-L1 were evaluated by immunohistochemistry(IHC).The associations of the SR-BI staining intensity with clinicopathological features and immune markers were determined by the chi-square test.Univariate and multivariate COX regression analyses were used to evaluate independent prognostic factors.Kaplan–Meier analyses were performed to plot the survival curve.Results:Our results indicated that SR-BI was expressed at higher levels in tumor tissues than in adjacent paracancerous tissues(p<0.001),and patients with high levels of SR-BI expression had a worse prognosis.Univariate and multivariate analyses revealed that high SR-BI expression was an independent factor for poor prognosis.The chi-square test determined that the expression of SR-BI was negatively correlated with CD4+T cells and CD8+T cells(CD4+T cells,p=0.013;CD8+T cells,p=0.021),and positively correlated with PD-L1(p=0.022).Finally,survival analysis revealed that CD4+T cells were associated with the prognosis of GC patients(p=0.019),and the combined survival analysis of SR-BI and CD4+T cells was also statistically significant(p=0.030).Conclusion:SR-BI is highly expressed in GC tissue and associated with poor prognosis.Moreover,SR-BI can also regulate the GC tumor immune microenvironment.

Unveiling clinical significance and tumor immune landscape of CXCL12 in bladder cancer: Insights from multiple omics analysis

Objective: The interplay between chemokine C-X-C motif ligand 12(CXCL12) and its specific receptors is known to trigger various signaling pathways, contributing to tumor proliferation and metastasis. Consequently,targeting this signaling axis has emerged as a potential strategy in cancer therapy. However, the precise role of CXCL12 in clinical therapy, especially in immunotherapy for bladder cancer(BCa), remains poorly elucidated.Methods: We gathered multiple omics data from public databases to unveil the clinical relevance and tumor immune landscape associated with CXCL12 in BCa patients. Univariate and multivariate Cox regression analyses were employed to assess the independent prognostic significance of CXCL12 expression and formulate a nomogram. The expression of CXCL12 in BCa cell lines and clinical tissue samples was validated using enzymelinked immunosorbent assays(ELISA) and immunohistochemistry(IHC).Results: While transcriptional expression of CXCL12 exhibited a decrease in nearly all tumor tissues, CXCL12 methylation expression was notably increased in BCa tissues. Single-cell RNA analysis highlighted tissue stem cells and endothelial cells as the primary sources expressing CXCL12. Abnormal CXCL12 expression, based on transcriptional and methylation levels, correlated with various clinical characteristics in BCa patients. Functional analysis indicated enrichment of CXCL12 and its co-expression genes in immune regulation and cell adhesion. The immune landscape analysis unveiled a significant association between CXCL12 expression and M2 macrophages(CD163~+ cells) in BCa tissues. Notably, CXCL12 expression emerged as a potential predictor of immunotherapy response and chemotherapy drug sensitivity in BCa patients.Conclusions: Taken together, these findings suggest aberrant production of CXCL12 in BCa tissues,potentially influencing the treatment responses of affected individuals.

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma:Relation to the immune cycle

BACKGROUND Various histological types of gastric carcinomas(GCs)differ in terms of their pathogenesis and their preexisting background,both of which could impact the tumor immune microenvironment(TIME).However,the current understanding of the immune contexture of GC is far from complete.AIM To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODS In total,50 GC cases were examined(15 cases of diffuse GC,31 patients with intestinal-type GC and 4 cases of mucinous GC).The immunophenotype of GC was assessed and classified as immune desert(ID),immune excluded(IE)or inflamed(Inf)according to CD8+cell count and spatial pattern.In addition,CD68+and CD163+macrophages and programmed death-ligand 1(PD-L1)expression were estimated.RESULTS We found that GCs with different histological differentiation demonstrated distinct immune contexture.Most intestinal-type GCs had inflamed TIMEs rich in both CD8+cells and macrophages.In contrast,more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+lymphocytes but abundant CD68+macrophages,while mucinous GC had an IE-TIME with a prevalence of CD68+macrophages and CD8+lymphocytes in the peritumor stroma.PD-L1 expression prevailed mostly in intestinal-type Inf-GC,with numerous CD163+cells observed.Therefore,GCs of different histological patterns have specific mechanisms of immune escape.While intestinal-type GC was more often related to PD-L1 expression,diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSION These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Apoptotic B16-F1 Cells Coated with Recombinant Calreticulin Mediated Anti-tumor Immune Response in Mice

Objective： To investigate the recombinant calreticulin （rCRT） mediated antitumor immune response. Methods： Cell proliferation was determined by MTT method, apoptosis was evaluated by DNA fragmentation and CRT expression and cell localization were assayed by western blotting, QT-RT-PCR and immunofluorescence assays. The mouse melanoma cell line B16-F1 was treated with polyamine analogue BENS to induce apoptosis and incubated with rCRT to get rCRT coated on the membrane, and then the cells were used to immune BALB/c mice as a cell-antigen. Immunized animals were rechallenged by live B16-F1 cells and then tumor generation ratio and the lactate dehydrogenase release assay were used to evaluate antitumor effects of rCRT-mediated immunity. Results： BENS induced apoptosis of B16-F1 cells without the redistribution of CRT within the cells. When B16-F1 cells coated with rCRT were used as cell-antigen to inoculate the animals, the mice obtained the ability in inhibiting proliferation of homologous tumor cells in vivo. Comparing with the positive control group, the splenocytes from those inoculated mice have an obvious enhancement on their cytolytic effects specifically against B16-F1 cells. Conclusion： rCRT coated on the cell surface can enhance immunogenicity of apoptotic tumor cells and mediated effective anti-tumor immunoresponse in mice.

A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment

Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment(TME).Here,we developed a pH/reactive oxygen species(ROS)dual-response system to enhance chemoimmunotherapy for melanoma.The system productively accumulated in tumors by specific binding of phenylboronic acid(PBA)to sialic acids(SA).The nanoparticles(NPs)rapidly swelled and released quercetin(QUE)and doxorubicin(DOX)upon the stimulation of tumor microenvironment(TME).The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice,significantly enhancing the effects of the combination.Our study revealed DOX was an ICD inducer,stimulating immune responses and promoting maturation of dendritic cells(DCs).Additionally,QUE served as a TME regulator by inhibiting the cyclooxygenase-2(COX2)-prostaglandin E2(PGE2)axis,which influenced various immune cells,including increasing cytotoxic T cells(CLTs)infiltration,promoting M1 macrophage polarization,and reducing regulatory T cells(Tregs)infiltration.The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment.This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma

Objective:Lung squamous cell carcinoma(LUSC)is associated with a low survival rate.Evidence suggests that bone morphogenetic proteins(BMPs)and their receptors(BMPRs)play crucial roles in tumorigenesis and progression.However,a comprehensive analysis of their role in LUSC is lacking.Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC.Methods:The“R/Limma”package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC,using data from TCGA,GTEx,and GEO databases.Concurrently,the“survminer”packages were employed to investigate their prognostic value and correlation with clinical features in LUSC.The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis(WGCNA).LASSO analysis was conducted to construct a prognostic risk model for LUSC.Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC.Furthermore,based on the tumor immune estimation resource database and tumor-immune system interaction database,the role of the core gene in the tumor microenvironment of LUSC was explored.Results:GDF10 had a significant correlation only with the pathological T stage of LUSC,and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC.A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes(HRASLS,HIST1H2BH,FLRT3,CHEK2,and ALPL)for LUSC.GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression.Conclusion:GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion

To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade,thus impeding HCC progression.After analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection list.PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell survival.Specifically,nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20,which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells.PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importinα/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20.Clinically,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in tumors.Clinically,our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.

Reprogramming the tumor immune microenvironment via nanomaterial-mediated dynamic therapy

Our improved knowledge of tumor immunology laid a solid foundation for the clinical use of tumor immunotherapies such as immune checkpoint blockers,and the efficacy of these drugs increased our confidence that immunomodulation was a viable way of treating cancer.The basis of immunotherapy is to break the immune escape of the tumor and resolve the immune suppressive microenvironment of tumors.Nanomaterial-mediated dynamic therapy(NDT)is an emerging immuno-regulatable type for tumor therapy,whose effects are mediated by increased cellular levels of reactive oxygen species(ROS).ROS is a potent trigger of immunogenic cell death,and this process initiates antitumor immunity.Nanomaterials for use in NDT can be engineered to interact with almost all cell types in the tumor microenvironment to remodel this environment.In this review,we systematically examined the effects of NDT on four major cell types in the tumor microenvironment,namely tumor cells,lymphocytes,myeloid cells,and tumor stromal cells.We believe that this review will improve researchers’understanding of the anti-tumor immunity triggered by NDT,and provide ideas and inspiration for how optimally designed NDT schemes can be used to target the cells in the tumor microenvironment.

Heterogeneity of the tumor immune microenvironment and clinical interventions

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

A Noninvasive Approach to Evaluate Tumor Immune Microenvironment and Predict Outcomes in Hepatocellular Carcinoma

It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis and prognosis,there are still lack of efective radiomic-based model to evaluate TIME status,let alone predict clinical outcome and immune checkpoint inhibitor(ICIs)response for hepatocellular carcinoma(HCC).In this study,we developed a radiomic model to evaluate TIME status within the tumor and predict prognosis and immunotherapy response.A total of 301 patients who underwent magnetic resonance imaging(MRI)examinations were enrolled in our study.The intra-tumoral expression of 17 immune-related molecules were evaluated using co-detection by indexing(CODEX)technology,and we construct Immunoscore(IS)with the least absolute shrinkage and selection operator(LASSO)algorithm and Cox regression method to evaluate TIME.Of 6115 features extracted from MRI,fve core features were fltered out,and the Radiomic Immunoscore(RIS)showed high accuracy in predicting TIME status in testing cohort(area under the curve=0.753).More importantly,RIS model showed the capability of predicting therapeutic response to anti-programmed cell death 1(PD-1)immunotherapy in an independent cohort with advanced HCC patients(area under the curve=0.731).In comparison with previously radiomicbased models,our integrated RIS model exhibits not only higher accuracy in predicting prognosis but also the potential guiding signifcance to HCC immunotherapy.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

IQGAP3 promotes the progression of glioma as an immune and prognostic marker

Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well understood.Methods:Various methods,including genetic differential analysis,single-cell analysis,ROC curve analysis,Cox regression,Kaplan-Meier analysis,and enrichment analysis,were employed to analyze the expression patterns,diagnostic potential,prognostic implications,and biological processes involving IQGAP3 in normal and tumor tissues.The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence.Additionally,the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3.Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms.Results:High IQGAP3 expression in gliomas is associated with an unfavorable prognosis,particularly in wild-type IDH and 1p/19q non-codeleted gliomas.Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle,PI3K/AKT signaling,p53 signaling,and PLK1-related pathways.Furthermore,IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma.BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy.In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells,with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression.Conclusion:IQGAP3 shows promise as a valuable biomarker for diagnosis,prognosis,and immunotherapeutic strategies in gliomas.

Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status

Hepatocellular carcinoma(HCC)is the most common primary tumor of the liver and has a high mortality rate.The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage.The recent description of the tumor microenvironment(TME)in HCC has provided a new concept of immunogenicity within the HCC.Virusrelated HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells.This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors(ICIs).In addition,the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity.Therefore,data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.

Exosomes as mediators of tumor immune escape and immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups.The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment(TME)into one with strong immunosuppression,facilitating the immune escape of HCC cells.Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes(e.g.,proteins and nucleic acids)for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming,ultimately creating a tumor-friendly microenvironment.Characterized by several intrinsic attributes,such as good stability(bilayer-like structure)and high biocompatibility(cell secretion),exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs,thus effectively triggering the HCC cell elimination by the immune system.This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.

Mitoxantrone-Mediated Apoptotic B16-F1 Cells Induce Specific Anti-tumor Immune Response

In the process of cell apoptosis induced by specific reagents,calreticulin(CRT)in endoplasmic reticulum is transferred and coated onto the cell membrane.As a sort of specific ligand,the CRT on the surface of apoptotic cells could mediate recognition and clearance of apoptotic cells by phagocytes.In this research we discovered that mitoxantrone could induce apoptosis of mouse melonoma B16-F1 tumor cells,accompanied by the membrane translocation and coating of CRT.When mitoxantrone-treated B16-F1 cells were used as antigen to inoculate mice,the mice acquired an ability to suppress proliferation of homologous tumor cells.Splenocytes from these mice showed an increased cytolytic effect on homologous B16-F1 cells but no such effect on non-homologous H22 tumor cells.All these results suggested that mitoxantrone-treated apoptotic B16-F1 cells could be used as a sort of cell vaccine to initiate effective anti-tumor immunoresponse in mice.

Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients.A deeper understanding of how metabolic reprogramming in the tumor microenvironment(TME)regulates immunity remains a major challenge to tumor eradication.It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function.Tumor cells compete with infiltrating immune cells for nutrients and metabolites.Notably,the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function,and elevated inhibitory signals may favor cancer immune evasion.The major energy sources that supply different immune cell subtypes also undergo reprogramming.We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies.In this context,targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.

Hyperbaric oxygen treatment on keloid tumor immune gene expression

Background:Hyperbaric oxygen treatment(HBOT)has been demonstrated to influence the keloid recurrence rate after surgery and to relieve keloid symptoms and other pathological processes in keloids.To explore the mechanism of the effect of HBOT on keloids,tumor immune gene expression and immune cell infiltration were studied in this work.Methods:From February 2021 to April 2021,HBOT was carried out on keloid patients four times before surgery.Keloid tissue samples were collected and divided into an HBOT group(keloid with HBOT before surgery[HK]group,n=6)and a non-HBOT group(K group,n=6).Tumor gene expression was analyzed with an Oncomine Immune Response Research Assay kit.Data were mined with R package.The differentially expressed genes between the groups were compared.Hub genes between the groups were determined and verified with Quantitative Real-time PCR.Immune cell infiltration was analyzed based on CIBERSORT deconvolution algorithm analysis of gene expression and verified with immunohistochemistry(IHC).Results:Inflammatory cell infiltration was reduced in the HK group.There were 178 upregulated genes and 217 downregulated genes.Ten hub genes were identified,including Integrin Subunit Alpha M(ITGAM),interleukin(IL)-4,IL-6,IL-2,Protein Tyrosine Phosphatase Receptor Type C(PTPRC),CD86,transforming growth factor(TGF),CD80,CTLA4,and IL-10.CD80,ITGAM,IL-4,and PTPRC with significantly downregulated expression were identified.IL-10 and IL-2 were upregulated in the HK group but without a significant difference.Infiltration differences of CD8 lymphocyte T cells,CD4 lymphocyte T-activated memory cells,and dendritic resting cells were identified with gene CIBERSORT deconvolution algorithm analysis.Infiltration levels of CD4 lymphocyte T cell in the HK group were significantly higher than those of the K group in IHC verification.Conclusion:HBOT affected tumor gene expression and immune cell infiltration in keloids.CD4 lymphocyte T cell,especially activated memory CD4+T,might be the key regulatory immune cell,and its related gene expression needs further study.

Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

There is a close connection between epigenetic regulation,cancer metabolism,and immunology.The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management.As an epigenetic regulator of histone acetylation,panobinostat can induce histone acetylation and inhibit tumor cell proliferation,as well as regulate aerobic glycolysis and reprogram intratumoral immune cells.JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression.Herein,we proposed a chemo-free,epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer.A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor.It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona.The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells(e.g.,tumor-associated macrophages).The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization.Consequently,lactic acid production was reduced and angiogenesis inhibited;TAM switched to an anti-tumor phenotype,and the anti-tumor function of the effector CD8+T cells was reinforced.The strategy provides a potential method for remodeling the tumor immune microenvironment(TIME).