scholarly journals Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ming Yi ◽  
Mengke Niu ◽  
Jing Zhang ◽  
Shiyu Li ◽  
Shuangli Zhu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Antigen Presentation ◽  
Antitumor Immunity ◽  
Antitumor Effect ◽  
Bispecific Antibody ◽  
Mixed Lymphocyte Reaction ◽  
Tumor Models ◽  
Cancer Antigen ◽  
Tumor Bearing ◽  
Sting Pathway

Abstract Background Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn2+) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods The effect of Mn2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results Mn2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn2+ plus anti-PD-L1 therapy, Mn2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion Combining Mn2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.

Polysaccharide from Eucheuma Gelatinae Enhance Immunocompetence against Murine H22 Tumor In Vivo

2014 ◽  
Vol 989-994 ◽  
pp. 1056-1059
Author(s):  
Juan Tang ◽  
Zhen Kong ◽  
Dong Yue Liu ◽  
An Jun Liu
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Antitumor Effect ◽  
Biological Activities ◽  
Tumor Bearing

New antitumor strategies are underway and play important roles in clinical trials for combating cancer in future. Eucheuma gelatinae contains a certain amount of polysaccharides, which has various biological activities. In this study, the antitumor effect of Eucheuma gelatinae polysaccharide on murine H22 tumor bearing mice has been investigated. Histological stain, flow cytometry and other methods are applied to evaluate the effects of Eucheuma gelatinae polysaccharide on immunocompetence in vivo. The data indicates that Eucheuma gelatinae polysaccharide has antitumor effect in vivo by enhancing immunocompetence of the tumor bearers.

scholarly journals 573 FS120, an OX40/CD137 tetravalent bispecific dual agonist antibody, synergistically increases the antitumor activity of anti-PD-1 in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A602-A602
Author(s):  
Matthew Lakins ◽  
Wenjia Liao ◽  
Emma McConnell ◽  
Quincy Kaka ◽  
Jennifer Ofoedu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Bispecific Antibody ◽  
Cell Activity ◽  
T Cell Proliferation ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Tumor Bearing ◽  
Mouse Tumor Models

BackgroundImmune checkpoint inhibitors have demonstrated durable clinical responses and an increase in overall survival for some patients with cancer. Next generation cancer immunotherapies, such as tumor necrosis factor receptor superfamily (TNFRSF) agonists, have potential to further improve on this success. FS120 is a tetravalent bispecific antibody targeting OX40 and CD137 (4-1BB), currently being evaluated in a Phase I clinical trial (NCT04648202). FS120 activates CD4+ and CD8+ T cells by concurrent binding to both targets via an FcgR-independent mechanism [1]. In preclinical tumor models, FS120 induced T cell proliferation and cytokine production associated with significant tumor regression, better than that observed with a monoclonal antibody combination. Here, we demonstrate the ability of FS120 to improve anti-PD-1 induced T cell activity, increasing tumor growth inhibition and survival, in syngeneic mouse tumor models, compared to monotherapy.MethodsFS120 < i >in vitro</i > activity in combination with anti-PD-1 was assessed by utilizing staphylococcal enterotoxin A (SEA) superantigen assays and mixed leukocyte reaction (MLR) assays. An anti-mouse OX40/CD137 bispecific antibody (FS120 surrogate) was tested in CT26 syngeneic mouse tumor models in combination with an anti-mouse PD-1 antibody to assess efficacy and pharmacodynamic endpoints, including T cell proliferation by < i>ex vivo</i> flow cytometry and serum cytokine levels.ResultsFS120 in combination with anti-PD-1 enhanced primary human T cell activity, when compared to either monotherapy, in both SEA and MLR assays. FS120 surrogate significantly improved survival of CT26 tumor-bearing mice treated with anti-mPD-1 antibody. FS120 surrogate and anti-PD-1 combination significantly enhanced serum interferon-gamma levels and increased proliferating granzyme B+ CD8+ T cells in the blood of tumor-bearing mice, when compared to either monotherapy treatments.ConclusionsFS120 combination with anti-PD-1 enhances T cell activity in multiple human primary immune assays. In combination with anti-PD-1, FS120 surrogate increased the antitumor efficacy with pharmacodynamic changes related specifically to T cell activation, when compared to monotherapies. These data support the development of FS120 in combination with anti-PD-1 in patients with hard-to-treat cancers who may not benefit fully from either treatment as a monotherapy.ReferencesGaspar M, Pravin J, Rodrigues L, Uhlenbroich S, Everett K L, Wollerton F, Morrow M, Tuna M, Brewis N. CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement. Cancer Immunol Res. 2020; (8) (6) 781–793Ethics ApprovalMurine studies were conducted under a U.K. Home Office License in accordance with the U.K. Animal (Scientific Procedures) Act 1986 and EU Directive EU 2010/63.

scholarly journals ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer

Nature Cancer ◽  
2021 ◽  
Author(s):  
Jiehui Deng ◽  
Aatish Thennavan ◽  
Igor Dolgalev ◽  
Ting Chen ◽  
Jie Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antigen Presentation ◽  
Antitumor Immunity

scholarly journals Importance of antibody isotypes in antitumor immunity by monocytes and complement using human‐immune tumor models

2021 ◽  
Author(s):  
Sandra Lara ◽  
Jessica C. Anania ◽  
Alexander Virtanen ◽  
Viktoria Stenhammar ◽  
Sandra Kleinau
Keyword(s):  
Antitumor Immunity ◽  
Tumor Models ◽  
Antibody Isotypes ◽  
Human Immune

scholarly journals Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models

2017 ◽  
Vol 7 (1) ◽  
pp. e1377873 ◽  
Author(s):  
Katherine E. Lewis ◽  
Mark J. Selby ◽  
Gregg Masters ◽  
Jose Valle ◽  
Gennaro Dito ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Interleukin 21 ◽  
Mouse Tumor Models

Quercetin enhances the antitumor effect of trichostatin A and suppresses muscle wasting in tumor-bearing mice

2018 ◽  
Vol 9 (2) ◽  
pp. 871-879 ◽  
Author(s):  
Shu-Ting Chan ◽  
Cheng-Hung Chuang ◽  
Yi-Chin Lin ◽  
Jiunn-Wang Liao ◽  
Chong-Kuei Lii ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Antitumor Effect ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Trichostatin A ◽  
Tumor Bearing ◽  
Muscle Protein Degradation

Quercetin prevents TSA-induced muscle wasting by down-regulating FOXO1 mediated muscle protein degradation.

scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

IκB kinase 2 but not NF-κB–inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 983-991 ◽  
Author(s):  
Evangelos Andreakos ◽  
Clive Smith ◽  
Claudia Monaco ◽  
Fionula M. Brennan ◽  
Brian M. Foxwell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
Dominant Negative ◽  
Allogeneic Mixed Lymphocyte Reaction ◽  
Iκb Kinase ◽  
Antigen Presenting

AbstractAlthough dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activation is central to that process, as overexpression of IκBα blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-κB–inducing components, NF-κB–inducing kinase (NIK), and IκB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell–derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)–induced NF-κB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity.

scholarly journals Tumor-specific CD8-positive T cell-mediated antitumor immunity is implicated in the antitumor effect of local hyperthermia

2018 ◽  
Vol 35 (1) ◽  
pp. 226-231 ◽  
Author(s):  
Ken Ando ◽  
Yoshiyuki Suzuki ◽  
Takuya Kaminuma ◽  
Yuya Yoshimoto ◽  
Takahiro Oike ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Antitumor Effect ◽  
Local Hyperthermia

The Effect of Sirtuin 2 (Sirt2) Overexpressing Bone Marrow Mesenchymal Stem Cells on the Growth of Human Epidermal Growth Factor Receptor 2 (Her-2) Breast Cancer Cells and Its Mechanism

2021 ◽  
Vol 11 (4) ◽  
pp. 778-785
Author(s):  
Xiaolin Chen ◽  
Yan Wang ◽  
Sunlu Jiang
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Caspase 3 ◽  
Tumor Bearing ◽  
Her 2 ◽  
Ifn Γ

Our study investigates the effect of high expression of Sirt2 in MSCs (MSCs-Sirt2) on Her-2 breast cancer cell proliferation. A mouse subcutaneous xenograft tumor model was established and MSCssirt2 analysis was performed on nude mice. TUNEL staining, flow cytometry, western-blot, real-time PCR and immunohistochemistry were used to detect cancer cell apoptosis. The number of NK cells infiltrated by flow cytometry detected the tumor tissue of tumor-bearing mice, and its killing activity on tumor-bearing mice was detected by isotope labeling and release method. The levels of TNF-α, IFN-γ, IL-8, IL-6 and IL-10 were detected by ELISA. Caspase-3 level was decreased in the MSCs group (P <0.01) while increased in the MSCs-sirt2 group (P <0.001). However, PCNA expression showed an opposite profile in the Her-2 group and MSCs-sirt2 group compared to Caspase-3 level (P <0.01). The tumor volume and weight in the MSCs-sirt2 group was significantly reduced (P < 0.01), while increased in the MSCs group significantly (P < 0.05). The number of Ki-67-positive tumor cells in MSCs-sirt2 group was significantly reduced (P <0.01) and increased in MSCs group (P < 0.001) with oppositive number of TUNEL-positive tumor cells in the MSCs-sirt2 group and MSCs group (P <0.01). IFN-γ level showed an upward trend (P <0.001). The NK cell toxicity of MSCs-Sirt2 group was significantly higher (P <0.001). MSCs-Sirt2 has an inhibitory effect on Her-2 breast cancer cell growth by enhancing the local inflammatory response of NK cells.

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