scholarly journals Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ming Li ◽  
Bingjie Hao ◽  
Menghuan Zhang ◽  
Russel J. Reiter ◽  
Shumeng Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Combined Treatment ◽  
Pulmonary Nodules ◽  
Residual Tumor ◽  
Antitumor Effects ◽  
Multiple Pulmonary Nodules ◽  
Link Type ◽  
Early Lung Cancer

AbstractSurgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn, identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931.

scholarly journals A novel radio-sensitization method for lung cancer therapy: enhanced radiosensitization induced by antigens/antibodies reaction after targeting tumor hypoxia using Bifidobacterium

2020 ◽  
Author(s):  
Juan Yang ◽  
Zhouxue Wu ◽  
Yao Chen ◽  
Chuanfei Hu ◽  
Dong Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Monoclonal Antibodies ◽  
Treatment Group ◽  
Tumor Growth ◽  
Combined Treatment ◽  
Proliferation Index ◽  
Bifidobacterium Infantis ◽  
Glut 1 ◽  
Pet Ct ◽  
Tnf Α

Abstract Background：The hypoxic microenvironment of solid tumors reduces the susceptibility of cancer cells to radiotherapy. Current treatments are focused on the development of anti-cancer agents that selectively target tumor cells with no toxicity to healthy tissue. Bacteria colonize and destroy tumors and have emerged as biological vectors that can survive in the tumor microenvironment. Methods：In this study, a Lewis lung carcinoma transplant mouse model was established and treated with a combination of bifidobacterium infantis (Bi), its specific monoclonal antibodies (Ab) and radiotherapy (RT). 18F-FDG PET/CT and 18F-FMISO PET/CT imaging were performed to monitor tumor growth and hypoxia in the tumor tissue. Phosphorylated histone (γ-H2AX), the proliferation index (Ki-67), platelet endothelial cell adhesion molecules (CD31), tumor necrosis factor-α (TNF-α), hypoxia inducible factor-1α (HIF-1α) and glucose transporter 1 (Glut-1) levels were assessed through immunohistochemistry. Results：The results showed that the combined treatment group (Ab+ Bi+ RT) displayed delayed tumor growth and prolonged the survival of mice. The combined treatment group also had lower levels of HIF-1α, Glut-1, and CD31 expression, and a lower uptake of FDG and FMISO. The tumors treated with the combination therapy also had lower levels of hypoxia, and increased γ-H2AX and TNF-α expression. Conclusion：Taken together, these data suggest that the combination of bifidobacterium infantis and its specific monoclonal antibodies can markedly improve the efficacy of radiotherapy for the treatment of lung cancer.

scholarly journals Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer

2020 ◽  
Vol 52 (2) ◽  
pp. 406-418
Author(s):  
Li-jun Liang ◽  
Chen-xi Hu ◽  
Yi-xuan Wen ◽  
Xiao-wei Geng ◽  
Ting Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Tumor Control ◽  
Abscopal Effect ◽  
Antitumor Effects ◽  
Term Survival ◽  
Secondary Tumor ◽  
Immunosuppressive Tumor Microenvironment

PurposeThis study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma.Materials and MethodsLewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed.ResultsFor the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen–specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved.ConclusionOur results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

scholarly journals Leveraging the Treg-intrinsic CTLA4–PKCη signaling pathway for cancer immunotherapy

2021 ◽  
Vol 9 (9) ◽  
pp. e002792
Author(s):  
Hsin-Yu Liu ◽  
Christophe Pedros ◽  
Kok-Fai Kong ◽  
Ann J Canonigo-Balancio ◽  
Wen Xue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Effector T Cells ◽  
Clinical Approach ◽  
Antitumor Effects ◽  
Tumor Implantation ◽  
Therapeutic Model

BackgroundOur previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch−/−) Tregs into Prkch+/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context.MethodsWe have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs).ResultsUsing two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16–F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch−/− CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16–F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies.ConclusionThese findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.

scholarly journals Akkermansia muciniphila Enhances the Antitumor Effect of Cisplatin in Lewis Lung Cancer Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Zhuo Chen ◽  
Xiang Qian ◽  
Shasha Chen ◽  
Xiaoxuan Fu ◽  
Guanjun Ma ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Therapeutic Efficacy ◽  
Combined Treatment ◽  
Receptor Interaction ◽  
Lewis Lung ◽  
Cancer Model ◽  
Lewis Lung Cancer ◽  
Antitumor Effects ◽  
Akkermansia Muciniphila ◽  
Lung Cancer Model

Recently, intestinal flora plays a vital role in the occurrence and development of tumors and there is link between cancer immunotherapy and Akkermansia muciniphila (Akk). However, the therapeutic efficacy of Akk in lung cancer remained unclear. Hence, our study is aimed at investigating the antitumor effects of cisplatin (CDDP) combined with Akk on lung cancer. Using the murine lung cancer model by subcutaneously inoculating Lewis lung cancer model, 50 mice were divided into five groups: normal, model, CDDP, CDDP+Akk, and CDDP+antibiotics. After treatment within 5 weeks, compared with the model group, the administered group improved the changes of tumor pathomorphology. Compared with the CDDP group, CDDP combining with Akk slowed down the growth of tumor volume, downregulated the levels of ki-67, p53, and factor-associated suicide (Fas) ligand proteins and upregulated Fas proteins, increased the levels of interferon-γ, interleukin-6, and tumor necrosis factor-α, and suppressed the expression of CD4+CD25+Foxp3+ Treg in mouse peripheral blood and spleen. In addition, transcriptome analysis indicated that Akk combining with CDDP increased obviously the levels of IFI27l2 and IGFBP7 and was related to those pathways including the cytokine-cytokine receptor interaction, Th17 cell differentiation, FOXO, JAK-STAT, and PI3K-Akt signaling pathways. These results suggested that the therapeutic efficacy of the combined treatment of Akk and CDDP was superior to the only CDDP treatment, which could enhance immune regulation and would be a promising strategy for the treatment of lung cancer.

Vaccination With Irradiated Induced Pluripotent Stem Cells Genetically Engineered To Produce GM-CSF Confers Potent T Cells-Mediated Antitumor Immunity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4492-4492 ◽  
Author(s):  
Hiroyuki Inoue ◽  
Ayumi Watanabe ◽  
Chika Sakamoto ◽  
Megumi Narusawa ◽  
Takafumi Hiramoto ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Antitumor Immunity ◽  
Es Cells ◽  
Ips Cells ◽  
Genetically Engineered ◽  
Antitumor Effects ◽  
Gm Csf ◽  
Csf Cells

Development of a novel therapeutic modality targeting cancer stem cells (CSCs) holds great promise for the eventual eradication of cancer. It was demonstrated that CSCs shared antigenic similarities with embryonic stem (ES) cells and the vaccination using ES cells could generate antitumor immunity. However, the use of ES cells raises potential immunological and ethical problematic issues. Recently, by the forced ectopic expression of defined transcription factors, autologous somatic cells were successfully reprogrammed into induced pluripotent stem (iPS) cells that closely resemble ESCs. We hypothesized that novel cell vaccines using mouse iPS cells genetically engineered to express the immunostimulatory cytokine of GM-CSF would cross-react CSC cells to induce antitumor immunity against poorly immunogenic syngeneic LLC mouse lung cancer cells, which would resolve such problematic issues. Our results of in vitro assays demonstrated that non-transmissible recombinant Sendai virus-mediated mouse GM-CSF gene transfer to iPSCs (iPS/GM-CSF) was effective to produce abundant GM-CSF in vitro and iPS/GM-CSF cells maintained their stemness in terms of morphology and antigenicity as evidenced by the expression of SSEA-1,Oct3/4 and alkaline phosphatase compared with unmodified iPS cells. Prophylactic iPSCs vaccine studies revealed that wild-type female mice subcutaneously vaccinated with irradiated iPS (ir.iPS) cells on weeks 1, 2, and 3 before the tumor challenge with LLC cells significantly suppressed the LLC tumor growth compared with untreated mice (p<0.05). Additionally, mice vaccinated with ir.iPS/GM-CSF cells significantly inhibited the tumor growth compared with mice treated with ir.iPS/GFP cells (p<0.05), showing that genetic manipulation of iPS cells with GM-CSF encoding gene potentiated the antitumor effect. Of note, no serious adverse events were observed with lack of liver and kidney dysfunctions as evidenced by biochemical analysis. Furthermore, therapeutic vaccinations with repeated ir.iPS/GM-CSF cells significantly inhibited the pre-established LLC tumor growth compared with untreated mice (p<0.05), with unaltered body weight. To address the effectors of the observed antitumor effects by ir.iPS/GM-CSF cells, we performed in vivo depletion experiments. The antitumor effects observed in mice treated with iPS/GM cells were significantly abrogated when CD4+ T cells- or CD8+ T cells were depleted, showing that iPS cells-based vaccines effectively generated T cells-mediated antitumor immunity. Lastly, we performed a cDNA microarray analysis to detect comparably expressed genes for the putative CSCs-associated antigens as a target of iPS cells-based vaccines on LLC cells, iPS cells, ir.iPS cells and ir.iPS/GM-CSF cells. Several sperm- or cell surface- specific antigens were predominantly expressed and shared between LLC cells and these iPS cell fractions, indicating that LLC cells and iPS cells may share CSCs-associated antigens. In conclusion, our results collectively demonstrate iPS cells-based vaccine can induce both prophylactic and therapeutic antitumor immunity in syngeneic mouse models, and indicate that this novel vaccine strategy may eliminate CSCs that shared antigenic similarities as a promising modality for cancer immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Biomarker for the Evaluation of Indeterminate Pulmonary Nodules for Early Lung Cancer Detectio

CHEST Journal ◽  
2011 ◽  
Vol 140 (4) ◽  
pp. 294A
Author(s):  
Nicolas Kahn ◽  
Michael Meister ◽  
Ralf Eberhardt ◽  
Thomas Muley ◽  
Philipp Schnabel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pulmonary Nodules ◽  
Early Lung Cancer

Effect of a nos inhibitor, t1023, in combination with γ-irradiation and cyclophosphamide on growth and metastasis of Lewis lung carcinoma

2019 ◽  
pp. 105-109
Author(s):  
М.В. Филимонова ◽  
В.М. Макарчук ◽  
Л.И. Шевченко ◽  
А.С. Филимонов
Keyword(s):  
Tumor Growth ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Statistical Significance ◽  
Combined Treatment ◽  
Lewis Lung ◽  
Γ Irradiation ◽  
Antitumor Effects ◽  
Nos Inhibitors ◽  
Nos Inhibitor

Цель работы - изучение антинеопластических эффектов при комбинированном воздействии ингибитора NOS Т1023 с γ-излучением и циклофосфамидом. Методика. В работе использован штамм эпидермоидной карциномы легких Льюиса. Выполнено 2 независимых эксперимента: в одном изучали антинеопластические эффекты при раздельном и комбинированном воздействии Т1023 и γ-излучения, в другом - при раздельном и комбинированном воздействии Т1023 и циклофосфамида. Особям 1-й опытной группы в обоих экспериментах с 7-х по 20-е сут роста карциномы ежедневно вводили соединение Т1023 в дозе 60 мг/кг внутрибрюшинно. В первом эксперименте животные 2-й опытной группы на 7-е сут роста неоплазии получали сеанс облучения (доза 5 Гр). Во втором эксперименте животным этой группы на 7-е сут роста неоплазии вводили однократно внутрибрюшинно циклофосфамид в дозе 100 мг/кг в виде 1,0% раствора фармакопейного препарата на основе 0,9% раствора натрия хлорида. Животным 3-й опытной группы в обоих экспериментах проводили соответствующие комбинированные воздействия по этим же схемам и в таких же дозах. Первое введение Т1023 на 7-е сут роста карциномы этим животным проводили через 4 ч после облучения или введения циклофосфамида. Влияние на рост опухоли оценивали по межгрупповым различиям объемов опухолевых узлов, длительности задержки роста и индексу торможения роста опухоли. Влияние на активность метастазирования карциномы оценивали по межгрупповым различиям числа легочных метастазов на 21-е сут роста опухоли и индексу ингибирования метастазирования. Статистическую оценку значимости межгрупповых различий количественных показателей проводили с помощью дисперсионного анализа Краскела-Уоллиса с применением Q-критерия Данна. Результаты. Показано, что воздействие Т1023, как в комбинации с γ-излучением, так и в комбинации с циклофосфамидом, сопровождается статистически значимым подавлением роста и метастазирования карциномы легких Льюис. При этом антинеопластические эффекты обоих комбинированных воздействий соответствовали аддитивному противоопухолевому и антиметастатическому действию ингибитора NOS, γ-излучения и циклофосфамида. Заключение. Полученные результаты отражают способность ингибиторов NOS повышать эффективность радио- и химиотерапии злокачественных новообразований, что свидетельствуют о перспективности дальнейшей разработки препаратов типа соединения Т1023. The aim was to study antineoplastic effects of a NOS inhibitor, T1023, in combination with γ-irradiation and cyclophosphamide. Methods. Epidermoid Lewis lung carcinoma (LLC) was used as a tumor model. Two independent experiments were performed. In the first experiment, antitumor effects of T1023 and γ-irradiation were studied individually and combined. In the second experiment, antitumor effects of T1023 and cyclophosphamide were studied individually and combined. In both experiments, mice from the first experimental group were daily injected with T1023 60 mg/kg from day 7 to 20. In the first experiment, animals of the second group were treated with γ-irradiation at 5 Gy on day 7 of tumor growth. In the second experiment, mice of the second group were injected with cyclophosphamide 100 mg/kg on day 7 of tumor growth. In both experiments, mice of the third group received a respective combined treatment according to the protocols described above. The first injection of T1023 was performed on day 7 after tumor transplantation at 4 hours after the irradiation or cyclophosphamide treatment. Antitumor effects were assessed by comparing the tumor size, duration of tumor growth delay, and the index of tumor growth inhibition in control and experimental groups. The effect of treatments on metastatic activity of carcinoma was evaluated by the intergroup difference in number of pulmonary metastases inhibition index on day 21 of tumor growth. Statistical significance was determined using the Kruskal-Wallis dispersion analysis with the Dunn Q-test. Results of the study showed that the T1023 treatment both in combination with γ-irradiation and with cyclophosphamide was associated with a significantly greater inhibition of tumor growth and metastasis. The antineoplastic effect of both combinations was consistent with the additive antitumor and antimetastatic effect of the NOS inhibitor, γ-radiation, and cyclophosphamide. Conclusion. The study showed the ability of NOS inhibitors to enhance the effectiveness of radio- and chemotherapy for malignant tumors and suggested a promising outlook for further development of T1023.

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