Abstract B11: Low-dose HMGN1 synergistically enhances antitumor immunity in CD4 depleting antibody-treated mice

2018 ◽  
Author(s):  
Chang-Yu Chen ◽  
Satoshi Ueha ◽  
Shoji Yokochi ◽  
Yoshiro Ishiwata ◽  
Haru Ogiwara ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Low Dose

scholarly journals Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3

2021 ◽  
Vol 9 (12) ◽  
pp. e002772
Author(s):  
Young Min Chung ◽  
Pragya P Khan ◽  
Hong Wang ◽  
Wen-Bin Tsai ◽  
Yanli Qiao ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protein Level ◽  
Antitumor Immunity ◽  
Low Dose ◽  
Antineoplastic Agent ◽  
Immune Checkpoint Blockade ◽  
Mouse Tumor ◽  
Programmed Death ◽  
L1 Protein

BackgroundStimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy.MethodsWe assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity.ResultsWe showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors.ConclusionWe show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.

Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma

2015 ◽  
Vol 356 (2) ◽  
pp. 743-750 ◽  
Author(s):  
Ah Ra Goh ◽  
Seung-Pil Shin ◽  
Na-Rae Jung ◽  
Chang-Hwan Ryu ◽  
Hyeon Seok Eom ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
Low Dose ◽  
Tonsillar Carcinoma

scholarly journals Effect of Modified Vaccinia Ankara–5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer

JAMA Oncology ◽  
2017 ◽  
Vol 3 (10) ◽  
pp. e172579 ◽  
Author(s):  
Martin Scurr ◽  
Tom Pembroke ◽  
Anja Bloom ◽  
David Roberts ◽  
Amanda Thomson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Antitumor Immunity ◽  
Low Dose

Abstract 1696: High-dose versus low-dose fractionated ionizing radiation to enhance antigen-specific antitumor immunity

2017 ◽  
Author(s):  
Megan V. Morisada ◽  
Ellen C. Moore ◽  
Jay A. Friedman ◽  
James W. Hodge ◽  
James B. Mitchell ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Antitumor Immunity ◽  
Low Dose ◽  
High Dose

scholarly journals Antitumor immunity of low-dose cyclophosphamide: changes in T cells and cytokines TGF-beta and IL-10 in mice with colon-cancer liver metastasis

2019 ◽  
Vol 8 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Xiao-Ming Huang ◽  
Nan-Rong Zhang ◽  
Xu-Tao Lin ◽  
Cai-Yan Zhu ◽  
Yi-Feng Zou ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Liver Metastasis ◽  
Antitumor Immunity ◽  
Low Dose ◽  
Survival Times ◽  
Expression Levels ◽  
Colon Cancer Liver Metastasis ◽  
Ifn Γ ◽  
Tgf Β1

Abstract Background The tumor immune microenvironment is one of the most important prognostic factors in liver metastasis from colorectal cancer. Low-dose cyclophosphamide (CTX) is widely believed to be involved in the modulation of the immune system. However, the underlying mechanism of low-dose CTX remains unknown. This study aimed to investigate the antitumor immunity of low-dose CTX in the treatment of colon-cancer liver metastasis. Methods Thirty mice were randomly divided into five groups. After liver metastasis was established in colon-cancer models, mice in the treatment groups were injected with low-dose CTX (20 mg/kg) at different time points. Liver and spleen tissues were examined for T-cell markers via flow cytometry. Interleukin (IL)-10 and transforming growth factor (TGF)-β1 expression levels in liver tissues were analysed by immunohistochemistry. Serum interferon (IFN)-γ and IL-10 levels were detected by enzyme-linked immunosorbent assay. An additional 20 mice were randomly allocated into two groups and the survival times were recorded. Results The expression levels of CD4+ T cells, CD8+ T cells, and IFN-γ were down-regulated, whereas those of IL-10 and TGF-β1 were up-regulated in liver metastasis from colon cancer in mice. Furthermore, the local and systemic microenvironments of the liver were altered, which led to reduced antitumor immune responses and subsequently liver metastasis. However, treatment with low-dose CTX reversed these effects. The survival times of mice treated with low-dose CTX were significantly longer than those of the other groups. Conclusions Low-dose CTX exerts its antitumor activity by changing the systemic and local immune microenvironments and enhancing immune regulation in mice. CTX could be used as a drug to prevent and treat liver metastasis from colon cancer.

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