Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Immune status and combined immunotherapy progression in Kirsten rat sarcoma viral oncogene homolog(KRAS)-mutant tumors

Kirsten rat sarcoma viral oncogene homolog(KRAS)is the most frequently mutated oncogene,occurring in various tumor types.Despite extensive efforts over the past 40 years to develop inhibitors targeting KRAS mutations,resistance to these inhibitors has eventually emerged.A more precise understanding of KRAS mutations and the mechanism of resistance development is essential for creating novel inhibitors that target specifically KRAS mutations and can delay or overcome resistance.Immunotherapy has developed rapidly in recent years,and in-depth dissection of the tumor immune microenvironment has led researchers to shift their focus to patients with KRAS mutations,finding that immune factors play an essential role in KRAS-mutant(KRAS-Mut)tumor therapy and targeted drug resistance.Breakthroughs and transitions from targeted therapy to immunotherapy have provided new hope for treating refractory patients.Here,we reviewed KRAS mutation-targeted treatment strategies and resistance issues,focusing on our in-depth exploration of the specific immune status of patients with KRAS mutations and the impact of body immunity following KRAS inhibition.We aimed to guide innovative approaches combining RAS inhibition with immunotherapy,review advances in preclinical and clinical stages,and discuss challenges and future directions.

NIR-triggered on-site NO/ROS/RNS nanoreactor:Cascade-amplified photodynamic/photothermal therapy with local and systemic immune responses activation

Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.

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.

Prognostic characterization of copper death-related immune checkpoint genes and analysis of immunologic and pharmacologic therapy in bladder cancer

Objective:Copper death-induced tumor cell death and immune checkpoint blockade therapy are highly selective.Combining their advantages and understanding their characteristics in bladder cancer is very important for the development of new targeted therapy.The identification of bladder cancer by screening the characteristic genes of copper death-related immune checkpoints provide a theoretical basis for the selection of adjuvant treatment options and the application of new targets.Methods:The expression samples of normal bladder tissue and bladder cancer were obtained from TCGA and GEO databases,and 13 cop-per death genes and 79 immune checkpoint genes were extracted from previous studies.The mRNA expression of prognostic genes was verified by qPCR.The copper death-related immune checkpoint genes were screened by correlation analysis to construct a prognostic model,and the differences in the efficacy of immunotherapy and chemotherapy between the high-risk group and the low-risk group were evaluated.Results:A prognostic model consisting of BTNL9,CD160,TNFRSF14 and TNFRSF18 was constructed.Its reliable predictive ability was proved in both databases,and qPCR showed that the expression levels of the four genes were significantly different between the normal group and the cancer cell group.The effect of immunotherapy in the lowrisk group was better than that in the high-risk group.Patients in the high-risk group had better chemotherapy efficacy.Conclusion:The copper death-related immune checkpoint gene model can accurately predict the prognosis of patients.Drug and immune analysis provide a basis for clinical treatment,and the discovery of potential targets provides a new solution for clinical decision-making.

Acupoint catgut-embedding therapy ameliorates DNCB-induced atopic dermatitis in BALB/c mice by regulating Th2 type immune response and reducing infiltration of CD4^(+)and CD8^(+)cells

Background:This study aimed to assess how acupoint catgut-embedding therapy influences Th2-type immune response and the infiltration of CD4^(+)and CD8^(+)cells in DNCB-induced atopic dermatitis in BALB/c mice.It also conducted an initial examination of the underlying molecular mechanisms.Methods:Seventy-two mice were randomly divided into four groups:normal control,DNCB-induced atopic dermatitis model(AD),AD with acupoint catgut-embedding treatment(ADA),and AD with sham-acupoint catgut-embedding treatment.After DNCB challenge to induce AD,the ADA group received acupoint catgut-embedding therapy treatment at Zusanli(ST 36)and Quchi(LI 11)acupoints every other week from day 8.Mice in the AD with sham-acupoint catgut-embedding treatment group underwent the same procedure as the ADA group but without catgut implantation.Severity was assessed using SCORAD on treatment days 1,10,and 20.On day 18,nine mice per group were euthanized,and the remaining on day 28.Histopathological changes were observed using hematoxylin-eosin and immunohistochemistry staining.TNF-α,IL-4,IL-6,and IL-13 levels were analyzed by ELISA,and GATA3 and STAT6 protein levels by western blot.Results:After 20 days of acupoint catgut-embedding therapy treatment,mice showed reduced dermatitis scores compared to DNCB-induced AD-like mice.Significant decreases occurred in serum IL-4,IL-6,IL-13,and TNF-αlevels.Skin analysis revealed marked reductions in CD4^(+)and CD8^(+)cell infiltration,as well as GATA3 and STAT6 protein levels.Conclusion:Acupoint catgut-embedding therapy may effectively alleviate atopic dermatitis by suppressing Th2 immune responses via the STAT6-GATA3 pathway and reducing CD4^(+)and CD8^(+)T cell infiltration in skin lesions.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

Efficacy evaluation and survival analysis of the combination of oxaliplatin plus Teysuno (SOX) with immune checkpoint inhibitors in the conversion therapy of locally advanced gastric cancer

Background:The efficacy of combining immune checkpoint inhibitors(ICIs)with chemotherapy in neoadjuvant therapy for locally advanced gastric cancer has been explored.However,limited research exists on its effectiveness in conversion therapy,and its superiority over standalone chemotherapy remains to be elucidated.This study aims to investigate the efficacy and survival outcomes of patients treated with ICIs in combination with conversion therapy for locally advanced gastric cancer.Methods:Retrospective data from patients with locally advanced gastric cancer treated with either oxaliplatin+S-1(SOX)alone or in combination with ICIs in conversion therapywere collected.Clinical andpathological characteristics,disease-free survival,andefficacy assessments in nonoperable patients were compared between the 2 treatment groups.Efficacy was further evaluated through dynamic changes in serum markers,and patients’quality of life was assessed using the QLQ-STO22(Gastric Cancer–Specific Quality of Life Questionnaire)quality-of-life measurement scale.Results:A total of 140 patients underwent conversion therapy:80 in the SOX alone group and 60 in the SOX combined with the ICIs group.There were no significant differences in baseline characteristics between the 2 groups.Compared with the SOX alone group,the SOX combined with ICIs group exhibited a higher conversion rate(83.3%vs 75%,P=0.23),R0 resection rate(90.0%vs 83.3%,P=0.31),pathological complete response(pCR)rate(18%vs 5%,P=0.02),median disease-free survival(21.4 vs 16.9 months,P=0.007),the objective response rate in nonoperable patients(60%vs 40%,P=0.301),and median progression-free survival time(7.9 vs 5.7 months,P=0.009).The QLQ-STO22 quality-of-life assessment revealed statistically significant improvements in pain,swallowing difficulties,and dietary restrictions in the combination therapy group compared with those in the monotherapy group.The enhanced efficacy of immune combination with SOX is evident,as demonstrated by the significantly prolonged surgical duration in operated patients(206.6±26.6 min vs 197.8±19.8 min,P=0.35)and intraoperative blood loss(158.9±21.2 mL vs 148.9±25.1 mL,P=0.59).No significant differences were observed in postoperative complications.Conclusions:Compared with the SOX conversion therapy regimen,SOX combined with ICIs demonstrated higher conversion rates,R0 resection rates,pathological response rates,and disease-free survival without increasing surgical difficulty or complications.Nonoperable patients also experienced longer progression-free survival and objective response rates.

Effects of different chemotherapy regimens before radical operation for lung cancer on cancer cell growth and anti-tumor immune response

Objective:To investigate the effects of different chemotherapy regimens before radical operation for lung cancer on cancer cell growth and antitumor immune response.Methods: A total of 180 patients with primary lung cancer who underwent surgery in this hospital between February 2013 and August 2017 were divided into the cisplatin group (n=93) who received cisplatin & paclitaxel chemotherapy and the lobaplatin group (n=87) who received lobaplatin & paclitaxel chemotherapy according to different preoperative neoadjuvant chemotherapy regimens. The differences among the expression of proliferation genes and apoptosis genes in tumor tissues as well as the contents of Th1/Th2 cytokines in serum were compared between the two groups.Results: Proliferation genes DDX17, GPx1, MACC1, RACK1 and SIRT1 mRNA expression levels in tumor tissue of lobaplatin group were lower than those of cisplatin group whereas LRRC3B mRNA expression level was higher than that of cisplatin group;apoptosis gene Fas, FasL and Caspase-3 mRNA expression levels were higher than those of cisplatin group whereas Survivin and Bcl-2 mRNA expression levels were lower than those of cisplatin group;serum Th1 cytokines IFN-γ and IL-12 contents were higher than those of cisplatin group whereas Th2 cytokines IL-5 and IL-10 contents were lower than those of cisplatin group.Conclusion: Lobaplatin chemotherapy before radical operation for lung cancer is more effective than cisplatin chemotherapy to inhibit the proliferation activity and enhance the apoptosis activity of lung cancer cells and optimize the anti-tumor immune response.

Effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapyn

Objective: To study the effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapy. Methods: Patients with advanced bladder cancer who received bladder infusion chemotherapy in the First People's Hospital of Ziyang between May 2014 and December 2016 were selected and divided into the control group without negative emotions, the anxiety group with anxiety, the depression group with depression and the anxiety depression group with both anxiety and depression according to the assessment results of HAMA scale and HAMD scale. The contents of tumor markers in serum, the contents of immune cells in peripheral blood and the expression of apoptosis genes in urine were detected during chemotherapy. Results: DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD-1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety group, depression group and anxiety depression group were significantly higher than those of control group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of control group, and DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD-1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety depression group were significantly higher than those of anxiety group and depression group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of anxiety group and depression group. Conclusion: The anxiety and depression in bladder cancer infusion chemotherapy can suppress the expression of apoptosis genes and the anti-tumor immune response to lead to more vigorous proliferation of cancer cells.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

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.

Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection

Hepatitis B virus （HBV） infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects. Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection： （1） These influence acquisition of chronic HBV carrier state, （2） They are important in the context of liver damages, （3） Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach （vaccine therapy）. The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV- specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.

Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes;therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyteassociated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreactive T cells, which are involved in autoimmune diseases. However, it is unknown whether attenuated activated healthy autologous T-cell immunization could increase anti-tumor immune responses. To this end, C57B1/6 mice were immunized with attenuated activated autologous T cells. The splenocytes from immunized mice showed a higher proliferative ability than that from naive mice. The special phenotype analysis showed that there were more CD8+ T cells and CD62L+ T cells in immunized mice after 24 h of culture with 10% fetal calf serum complete medium in vitro (P〈0.01). These results demonstrated that this immunization may activate T cells in vivo. Furthermore, the splenocytes from immunized mice revealed resistance to activation-induced cell death (AICD) in vitro. To further study the relative genes that are responsible for the higher proliferation and resistance to AICD, the expression of Fas/Fas ligand (FasL) and GADD4513 was measured by real-time PCR. The results indicated that GADD45β transcription was higher in the splenocytes from immunized mice than that in the naive mice. In addition, the Fas expression showed a parallel higher, but FasL did not change obviously. To investigate the biologic functions induced by immunization in vivo, a tumor model was established by EL-4 tumor cell inoculation in C57/B1 mice. Mice receiving autologous T-cell immunization had significantly inhibited tumor growth in vivo (P〈0.01). This study implicated that immunization with attenuated activated autologous T cells enhances anti-tumor immune responses that participate in tumor growth inhibition.

Immune response after photodynamic therapy increases anti-cancer and anti-bacterial effects

Photodynamic therapy(PDT) is a clinically approved procedure for treatment of cancer and infections. PDT involves systemic or topical administration of a photosensitizer(PS), followed by irradiation of the diseased area with light of a wavelength corresponding to an absorbance band of the PS. In the presence of oxygen, a photochemical reaction is initiated, leading to the generation of reactive oxygen species and cell death. Besides causing direct cytotoxic effects on illuminated tumor cells, PDT is known to cause damage to the tumor vasculature and induce the release of pro-inflammatory molecules. Pre-clinical and clinical studies have demonstrated that PDT is capable of affecting both the innate and adaptive arms of the immune system. Immune stimulatory properties of PDT may increase its beneficial effects giving the therapy wider potential to become more extensively used in clinical practice. Be-sides stimulating tumor-specific cytotoxic T-cells capable to destroy distant untreated tumor cells, PDT leads to development of anti-tumor memory immunity that can potentially prevent the recurrence of cancer. The immunological effects of PDT make the therapy more effective also when used for treatment of bacterial infections, due to an augmented infiltration of neutrophils into the infected regions that seems to potentiate the outcome of the treatment.

Immune response induced by hematoporphyrin derivatives mediated photodynamic therapy:Immunogenic cell death and elevated costimulatory molecules

Photodynamic therapy(PDT)not only destroys tumor cells directly but also induced anti-tumor immune response through damage-associated molecular patterns(DAMPs).It is reported that anti-tumor response was associated with light dose and photosensitizer used in PDT.In this study,4T1 tumor cells were implanted on both the right and left flanks of mice.Only the right tumor was treated by HpD-PDT,while the left tumor was not irradiated.The anti-tumor immune response induced by HpD-PDT was investigated.The expression of DAMPs and costimulatory molecules induced by HpD-PDT were tested by immuno fluorescence and flow cytometry in vivo.Different light doses of PDT were designed to treat 4T1 cells.The killing effect was assessed by CCK-8 kit and apoptosis kit.The expression of DAMPs on 4T1 cells after HpDPDT were evaluated by flow cytometry,western blot and ATP kit.This study showed that CD4^(+)T,CD8^(+)T and the production of IFN-γwere increased significantly on day 10 in righttumor after PDT treatment compared with control group.HpD-PDT enhanced the expression of calreticulin(CRT)on tumor tissue.Importantly,co-stimulatory molecular OX-40 and 4-1BB were elevated on CD8^(+)T cells.In vitro,immunogenic death of 4T1 cells was induced after PDT.Besides,the expression of DAMPs increased with the increasing of energy density.This study indicates that anti-tumor immune effect was induced by HpD-PDT.The knowledge of the involvement of CRT,ATP and co-stimulatory molecules uncovers important mechanistic insight into the anti-tumor immunogenicity.It was the first time that co-stimulatory molecules were investigated and found to elevate after PDT.