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CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment via Cytotoxic T Cells.

ABSTRACT: Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (?PD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8⁺ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME.

SUBMITTER: Park S

PROVIDER: S-EPMC7874050 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment <i>via</i> Cytotoxic T Cells.

Park Songyi S Oh Ji Hoon JH Park Dong Jin DJ Zhang Haiying H Noh Minyoung M Kim Yeomyung Y Kim Ye-Seul YS Kim Hyejeong H Kim Young-Myeong YM Ha Sang-Jun SJ Kwon Young-Guen YG

Frontiers in immunology 20210126

Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within ...[more]

PMID: 33584714

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Project description:BACKGROUND:The efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors. METHODS:Domatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and -stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade. RESULTS:Domatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14?days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-? and pembrolizumab response signatures in individual tumor samples. CONCLUSION:In summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

Project description:BackgroundAge-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption and vascular dementia, are emerging as potential risks for many neurodegenerative diseases. Therefore, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing brain injury. Our previous study showed that CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic reperfusion injury, and promoted the normalization of tumor vasculature. Here, we evaluated the effects of CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain.ResultsIn this study, we investigated the protective effects of CU06-1004 against oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress-induced model of cellular injury. Compared with H2O2 treatment alone, pretreatment of HBMECs with CU06-1004 considerably reduced oxidative stress-induced cytotoxicity, reactive oxygen species generation, senescence-associated β-galactosidase activity, senescence marker expression, and the expression levels of inflammatory proteins. Based on the observed cytoprotective effects of CU06-1004 in HBMECs, we examined whether CU06-1004 displayed protective effects against cerebrovascular aging in mice. Long-term administration of CU06-1004 alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in the aged mouse brain. CU06-1004 supplementation also reduced the extravasation of plasma IgG by improving BBB integrity in the aged mouse brain, associated with reductions in neuronal injury. A series of behavioral tests also revealed improved motor and cognitive functions in aged mice that received long-term CU06-1004 administration.ConclusionsThese findings suggest that CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age.

Project description:Colorectal cancer (CRC), mostly categorized as a low immunogenic microsatellite-stable phenotype bearing complex immunosuppressive tumor microenvironment (TME), is highly resistant to immunotherapy. Seeking safe and efficient alternatives aimed at modulating tumor immunosuppressive TME to improve outcome of CRC is highly anticipated yet remains challenging. Methods: Enlightened from the drug complementary art in traditional Chinese medicine, we designed a self-assembled nanomedicine (termed LNT-UA) by the natural active ingredients of ursolic acid (UA) and lentinan (LNT) through a simple nano-precipitation method, without any extra carriers, for CRC immunotherapy. Results: UA induces immunogenic cell death (ICD), while LNT further promotes dendritic cell (DC) maturation and repolarizes tumor-associated macrophage (TAM) from a protumorigenic M2 to an antitumor M1 phenotype. Co-delivery of UA and LNT by LNT-UA effectively reshapes the immunosuppressive TME and mobilizes innate and adaptive immunity to inhibit tumor progression in the CT26 CRC tumor model. Following the principle of integrative theoretical system of traditional Chinese medicine (TCM) on overall regulation, the further combination of LNT-UA and anti-CD47 antibody (αCD47) would reinforce the antitumor immunity by promoting phagocytosis of dying tumor cells and tumor-associated antigens (TAAs), leading to effective suppression of both primary and distant tumor growth with 2.2-fold longer of median survival time in the bilateral tumor model. Most notably, this combination effect is also observed in the spontaneous CRC model induced by chemical carcinogens, with much less and smaller size of tumor nodules after sequential administration of LNT-UA and αCD47 through gavage and intraperitoneal injection, respectively. Conclusions: This study provides a promising self-assembled traditional Chinese nanomedicine to improve immunotherapy for CRC, which might be applicable for future clinical translation.

Project description:BackgroundAcute lung injury (ALI) is a life-threatening condition that fundamentally results from inflammation and edema in the lung. There are no effective treatments available for clinical use. Previously, we found that as a leakage blocker CU06-1004 prevents endothelial barrier disruption and enhances endothelial cell survival under inflammatory conditions. In this study, we aimed to elucidate the effect of CU06-1004 in terms of prevention of inflammation and endothelial dysfunction in an ALI mouse model.MethodsAn ALI model was established that included intraperitoneal administration of LPS. Following LPS administration, survival rates and lung wet/dry ratios were assessed. Histological analysis was performed using hematoxylin and eosin staining. Scanning electron microscopy was used to examine alveolar and capillary morphology. Cytokines such as IL-1β, IL-6, and TNF-α were analyzed using an ELISA assay of bronchoalveolar lavage fluid (BALF) and serum. Neutrophil infiltration was observed in BALF using Wright-Giemsa staining, and myeloperoxidase (MPO) activity was assessed. Pulmonary vascular leakage was confirmed using Evans-blue dye, and the expression of junctional proteins was evaluated using immunofluorescent staining. Expression of adhesion molecules was observed using immunofluorescence staining. NF-κB activation was determined using immunohistochemistry and western blot analysis.ResultsSurvival rates and pulmonary edema were ameliorated with CU06-1004 treatment. Administration of CU06-1004 normalized histopathological changes induced by LPS, and alveolar-capillary wall thickening was reduced. Compared with the LPS-challenged group, after CU06-1004 treatment, the infiltration of immune cells was decreased in the BALF, and MPO activity in lung tissue was reduced. Similarly, in the CU06-1004 treatment group, pro-inflammatory cytokines were significantly inhibited in both BALF and serum. Evans-blue leakage was reduced, and the expression of junctional proteins was recovered in the CU06-1004 group. Adhesion molecules were downregulated and NF-κB activation was inhibited after CU06-1004 treatment.ConclusionsThese results suggested that CU06-1004 had a therapeutic effect against LPS-induced ALI via alleviation of the inflammatory response and protection of vascular integrity.

Dataset Information

CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment via Cytotoxic T Cells.

Publications

CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment <i>via</i> Cytotoxic T Cells.

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