Polarization of tumor-associated macrophage phenotype via porous hollow iron nanoparticles for tumor immunotherapy in vivo

Nanoscale ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 130-144 ◽  
Author(s):  
Ke Li ◽  
Lu Lu ◽  
Chencheng Xue ◽  
Ju Liu ◽  
Ye He ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Iron Nanoparticles ◽  
Tumor Immunotherapy ◽  
Macrophage Phenotype ◽  
Tumor Associated Macrophage ◽  
Immunosuppressive Microenvironment ◽  
M1 Type

PHNPs and 3-MA re-polarize TAMs to M1-type by activating the protein of NF-κB p65 and then remodelling the immunosuppressive microenvironment, thus activating immune response and inhibiting tumor growth.

Reprogrammed M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 extends lifespan of mice with experimental carcinoma

2017 ◽  
pp. 4-9
Author(s):  
С.В. Калиш ◽  
С.В. Лямина ◽  
А.А. Раецкая ◽  
И.Ю. Малышев
Keyword(s):  
Tumor Growth ◽  
Culture Medium ◽  
Ehrlich Carcinoma ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Ec Cells ◽  
Experimental Carcinoma

Цель исследования. Репрограммирование М1 фенотипа макрофагов с ингибированными факторами транскрипции М2 фенотипа STAT3, STAТ6 и SMAD и оценка их влияния на развитие карциномы Эрлиха (КЭ) in vitro и in vivo. Методика. Рост опухоли иницировали in vitro путем добавления клеток КЭ в среду культивирования RPMI-1640 и in vivo путем внутрибрюшинной инъекции клеток КЭ мышам. Результаты. Установлено, что M1макрофаги и in vitro, и in vivo оказывают выраженный противоопухолевый эффект, который превосходит антиопухолевые эффекты М1, M1, M1 макрофагов и цисплатина. Заключение. М1 макрофаги с ингибированными STAT3, STAT6 и/или SMAD3 эффективно ограничивают рост опухоли. Полученные данные обосновывают разработку новой технологии противоопухолевой клеточной терапии. Objective. Reprogramming of M1 macrophage phenotype with inhibited M2 phenotype transcription factors, such as STAT3, STAT6 and SMAD and assess their impact on the development of Ehrlich carcinoma (EC) in vitro and in vivo . Methods. Tumor growth in vitro was initiated by addition of EC cells in RPMI-1640 culture medium and in vivo by intraperitoneal of EC cell injection into mice. Results. It was found that M1 macrophages have a pronounced anti-tumor effect in vitro , and in vivo , which was greater than anti-tumor effects of M1, M1, M1 macrophages and cisplatin. Conclusion. M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 effectively restrict tumor growth. The findings justify the development of new anti-tumor cell therapy technology.

Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth

Nanoscale ◽  
2020 ◽  
Vol 12 (43) ◽  
pp. 22268-22280
Author(s):  
Hui Shan ◽  
Wenlong Dou ◽  
Yu Zhang ◽  
Mi Qi
Keyword(s):  
Tumor Growth ◽  
Intravenous Injection ◽  
Inhibit Tumor Growth ◽  
Cpg Oligodeoxynucleotides ◽  
Tumor Associated Macrophage ◽  
M1 Phenotype ◽  
M1 Type ◽  
M2 Phenotype

Novel M2pep-rHF-CpG nanoparticles repolarize the M2-type TAMs to M1-type and inhibit tumor growth after intravenous injection.

scholarly journals IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi125-vi125
Author(s):  
Tyler Alban ◽  
Defne Bayik ◽  
Balint Otvos ◽  
Matthew Grabowski ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Signaling Axis ◽  
Immunosuppressive Microenvironment ◽  
And Function

Abstract The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.

Programming the anti-tumor immune response in vitro and its application to stop the growth of tumor cells and prolonging the lifespan of mice with carcinoma in vivo

2017 ◽  
pp. 67-73
Author(s):  
С.В. Калиш ◽  
С.В. Лямина ◽  
А.А. Раецкая ◽  
О.П. Буданова ◽  
И.Ю. Малышев
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Tumor Cells ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Ec Cells ◽  
Growth Of Tumor ◽  
Immune Response In Vitro

Цель - представить доказательства правомерности гипотезы, что комбинированный пул репрограммированных in vitro макрофагов и лимфоцитов будет эффективно ограничивать пролиферацию опухолевых клеток in vitro , а при введении в организм будет существенно ограничивать развитие опухоли in vivo . Методика. Размножение опухолевых клеток инициировали in vitro путем добавления клеток карциномы Эрлиха (КЭ) в среду культивирования RPMI-1640. Развитие асцитной опухоли in vivo воспроизводили путем внутрибрюшной инъекции клеток КЭ мышам. Результаты. Установлено, что M3 макрофаги вместе с антиген-репрограммированными лимфоцитами оказывают выраженный противоопухолевый эффект и in vitro, и in vivo , который был существеннее противоопухолевого эффекта цисплатина. Заключение. Факты, свидетельствующие, что М3 макрофаги в сочетании с in vitro антиген-репрограммированными лимфоцитами значительно подавляют рост опухоли in vivo , делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли путем предварительного программирования противоопухолевого иммунного ответа «в пробирке». Aim. To test a hypothesis that a combined pool of in vitro reprogrammed macrophages and lymphocytes will effectively limit growth of tumor cells in vitro , and injections of these cells into the body will considerably limit development of a tumor in vivo . Methods. Tumor growth was initiated in vitro by addition of Ehrlich carcinoma (EC) cells to the RPMI-1640 cell culture medium and in vivo by intraperitoneal injection of EC cells into mice. Results. M3 macrophages in combination with antigen-reprogrammed lymphocytes exerted a pronounced antitumor effect both in vitro and in vivo, which was superior to the effect of cisplatin. Conclusion. M3 macrophages in combination with in vitro antigen-reprogrammed lymphocytes significantly inhibited the tumor growth in vivo . This fact justifies development of a clinical version of the tumor growth restricting biotechnology using pre-programming of the antitumor immune response in vitro .

Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40+ and CD40− plasmacytoma cells

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 200-207 ◽  
Author(s):  
Gianpietro Dotti ◽  
Barbara Savoldo ◽  
Patricia Yotnda ◽  
Donna Rill ◽  
Malcolm K. Brenner
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cd40 Ligand ◽  
Additional Treatment ◽  
Antitumor Immune Response ◽  
Tumor Growth Inhibition ◽  
Protective Effects ◽  
Transgenic Expression

Abstract Because tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40− myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8+or CD4+ lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40+ and CD40− tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40+ or CD40− tumors and may be of therapeutic value for both types of myeloma in humans.

scholarly journals TMOD-32. GL261 LUCIFERASE-EXPRESSING CELLS ELICIT AN ANTI-TUMOR IMMUNE RESPONSE: AN EVALUATION OF MURINE GLIOMA MODELS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi269-vi270
Author(s):  
Victoria Sanchez ◽  
John Lynes ◽  
Stuart Walbridge ◽  
Xiang Wang ◽  
Nancy Edwards ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Tumor Growth ◽  
Median Survival ◽  
In Vivo Evaluation ◽  
Kaplan Meier ◽  
Long Term Survivors

Abstract Preclinical models that reliably recapitulate the immunosuppressive properties of human gliomas are essential to assess immune-based therapies. Intracranially injected GL261 cells are widely used as an immunocompetent animal model of glioma, but it is common practice to transfect these with luciferase to facilitate tumor monitoring during treatment. Our group has previously shown that the luciferase-expressing GL261 Red-FLuc cells create an inflammatory response when implanted intracranially. Now, we additionally explore the inflammatory response of GL261-Luc2 cells and demonstrate a similar host immune response occurs with this model as well. In our in vivo evaluation, C57BL/6 mice underwent stereotaxic, intracranial implantation with GL261, GL261 Red-FLuc or GL261-Luc2 cells at doses of 5x104cells/5mL or 3x105cells/5uL.MRIs were performed to monitor relative tumor growth. To assess intrinsic differences between cell lines, in vitro cytokine profiles were evaluated by proteome microarray. Kaplan-Meier survival analyses demonstrated median survival for mice implanted with GL261 cells at 5x104cells was 18 to 21 days. The GL261-Red FLuc implanted mice cells did not reach median survival at either tumor dose with greater than 60% of mice termed long-term survivors. Finally, mice injected with GL261-Luc2 cells at 3x105cells reached median survival at 23 days, but median survival was significantly prolonged for mice implanted with GL261-Luc2 at a dose of 5x104cells (37 days, with 40% becoming long-term survivors) compared to GL261 implanted mice. MRIs reveal differences in tumor growth that correspond with the differences in median survival between groups. In addition, proteomic analyses revealed significantly elevated inflammatory cytokines such as IFN-gamma, IL-7 and TNF-alpha in the supernatants of the GL261 Red-FLuc cells and GL261-Luc2 cells. Further immune characterization is ongoing. Our data suggests that GL261 Red-FLuc and GL261-Luc2 murine models elicit an anti-tumor immune response by increasing pro-inflammatory modulators which stimulate the tumoricidal function of immune cells in the tumor microenvironment.

scholarly journals Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3054
Author(s):  
Kyra E. de Goede ◽  
Sanne G. S. Verberk ◽  
Jeroen Baardman ◽  
Karl J. Harber ◽  
Yvette van Kooyk ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Inflammatory Responses ◽  
Therapy Response ◽  
Tumor Type ◽  
Dependent Manner ◽  
Macrophage Phenotype ◽  
Atp Citrate Lyase ◽  
Promising Therapeutic Target

Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inflammatory responses in vitro, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.

scholarly journals 869 Locally administered immunotherapy self-delivering RNAi PH-762 results in abscopal clearance of untreated distal tumors, suggesting systemic immune response, in a murine hepatocarcinoma model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A910-A910
Author(s):  
Benjamin Cuiffo ◽  
Melissa Maxwell ◽  
Dingxue Yan ◽  
Brianna Rivest ◽  
James Cardia ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Mechanism Of Action ◽  
Systemic Toxicity ◽  
Published Data ◽  
Abscopal Effect ◽  
Systemic Immune Response ◽  
In Vivo Efficacy

BackgroundThe development of locally administered immune checkpoint inhibition (ICI) holds potential promise for enhanced activity and decreased systemic toxicity, but such an approach is challenging with the available ICI antibodies. We have previously shown that the intratumoral (IT) delivery of PH-762, a self-delivering RNAi compound targeting PD-1 based on proprietary INTASYL™ technology, can significantly inhibit tumor growth associated with changes in the immune cell population in the tumor microenvironment towards an anti-tumor phenotype. We present data showing that IT administration of PH-762 not only inhibits local tumor growth but can also elicit an abscopal effect in distal untreated tumors. The in vivo efficacy and in vitro mechanism of action support the generation of a PH-762 driven systemic anti-tumor immune response. Therefore, ICI using INTASYL is an alternative to antibody drugs for immunotherapy.MethodsTo assess in vivo efficacy, Hepa1–6 cells were implanted subcutaneously into the flanks of C57BL/6J mice. Vehicle (PBS) or murine targeting PH-762 (mPH-762) were administered IT on Days 1, 4, 7, 10 and 14. To determine an abscopal effect cells were also implanted into the opposite flank but left untreated. Tumor volumes and body weights were recorded. In addition, in vitro mechanism of action studies were performed with CD3-stimulated human pan T cells. PD-1 mRNA knockdown was assessed by qRT-PCR; PD-1 protein expression by flow cytometry; and T cell function by cytokine release.ResultsTreatment with IT administered mPH-762 significantly inhibited tumor growth compared with vehicle treated control tumors. Furthermore, the growth of the untreated bilateral tumor was significantly reduced with 80% of these tumors showing complete regression. Mechanism of action studies showed potent and durable silencing of PD-1. Increased release of IFN-γ, CXCL10, and IL-6 and suppression of IL-10 release were indicators of an enhanced immune response.ConclusionsThese data show that silencing PD-1 with IT administration of mPH-762 not only inhibits growth of treated tumors but elicits an abscopal effect leading to cure of distal tumors. This data and other recently published data showing evidence of a specific antitumor immune response in a tumor rechallenge model after prior treatment with INTASYL compounds, demonstrate the desired systemic immune response can be obtained with local administration of PH-762. INTASYL represent an alternative to antibody therapy for IT checkpoint blockade with potential for improved efficacy and reduced systemic toxicity which will be investigated in an upcoming clinical trial.

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