Cancer environmental immunotherapy: starving tumor cell to death by targeting TGFB on immune cell

The blockage of intersectional communication between tumor and its metabolic and immune microenvironment is now considered a promising solution in treating cancer. Tumors have been identified as a special type of “wounds” that do not heal. Recent studies demonstrate that the lack of the transforming growth factor beta (TGFB) signaling pathway in CD4+ helper T cells induces the remodeling of the intratumoral vascular tissue, like healing “wounds” in damaged tissues caused by tumor overgrowth, which consequently prevents tumor cells from receiving the required nutrients in their microenvironment. TGFB blockade thereby promotes damaged tissue healing, causing tumor cell death as a result of starvation, ultimately obtaining an effective anticancer immunotherapy immune response. Here, we comment on the TGFB-mediated crosstalk between immune system and nutritional supply, highlighting cancer immunotherapeutic strategies targeting environmental immune-metabolism interplay. Cancer environmental immunotherapy targeting TGFB might therefore become one of the most promising treatment strategies for patients with cancer.

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Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions

Surgery ◽

10.1067/msy.2003.125 ◽

2003 ◽

Vol 133 (5) ◽

pp. 568-579 ◽

Cited By ~ 6

Author(s):

David H. Berger ◽

Christine A. O'Mahony ◽

Hongmiao Sheng ◽

Jinyi Shao ◽

Daniel Albo ◽

...

Keyword(s):

Growth Factor ◽

Tumor Cell ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Cell Matrix ◽

Matrix Interactions ◽

Growth Factor Beta ◽

Cell Matrix Interactions ◽

Cell Cell

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Dysregulated miR-142, -33b and -423 in granulosa cells target TGFBR1 and SMAD7: a possible role in polycystic ovary syndrome

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz014 ◽

2019 ◽

Vol 25 (10) ◽

pp. 638-646 ◽

Cited By ~ 11

Author(s):

Yan Li ◽

Yungai Xiang ◽

Yuxia Song ◽

Lijing Wan ◽

Guo Yu ◽

...

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Polycystic Ovary Syndrome ◽

Granulosa Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Growth Factor Beta ◽

Tgfb Signaling

Abstract It is well established that microRNA (miRNA) expression profiles are altered in patients with polycystic ovary syndrome (PCOS). In addition, abnormal transforming growth factor beta (TGFB) signaling in granulosa cells is related to the pathological conditions of PCOS. However, the function of dysregulated miRNAs in PCOS is still unclear. In this study, we aimed to elucidate the roles of specific miRNAs in PCOS. We collected follicular fluid from 46 patients with PCOS and 32 healthy controls. Granulosa cells (GCs) were separated and the levels of six candidate miRNAs were determined by quantitative RT-PCR. The direct targets of three dysregulated miRNAs were predicted using bioinformatic tools and confirmed using a dual luciferase assay and immunoblotting. The biological function of three dysregulated miRNAs in primary GCs was determined using a cell proliferation assay and flow cytometry. We found that miR-423 expression was downregulated (P = 0.038), and the levels of miR-33b (P = 0.032) and miR-142 (P = 0.021) were upregulated in GCs from patients with PCOS, compared to controls. miR-423 directly repressed SMAD family member 7 (SMAD7) expression, while transforming growth factor beta receptor 1 (TGFBR1) was a direct target of both miR-33b and miR-142. An RNA oligonucleotide mixture containing miR-423 inhibitor, miR-33b mimic, and miR-142 mimic repressed TGFB signaling, promoted cell proliferation (P = 0.0098), repressed apoptosis (P = 0.027), and increased S phase cell numbers (P = 0.0036) in primary cultures of GCs, compared to the cells treated with a sequence scrambled control RNA oligonucleotide. This study unveiled the possible roles of three miRNAs in PCOS and might provide candidate biomarkers for PCOS diagnosis while in vivo functional studies, using transgenic or knockout mouse models, are expected to confirm the roles of dysregulated miRNAs in the pathogenesis of PCOS.

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Transforming of the Tumor Microenvironment: Implications for TGF-βInhibition in the Context of Immune-Checkpoint Therapy

Journal of Oncology ◽

10.1155/2018/9732939 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Stefanie Löffek

Keyword(s):

Tumor Microenvironment ◽

Transforming Growth Factor Beta ◽

Immune Checkpoint ◽

Transforming Growth Factor ◽

Treatment Strategies ◽

Therapy Response ◽

Initial Therapy ◽

Therapeutic Benefit ◽

Immune Checkpoint Blockade ◽

Oncogenic Signaling

Significant breakthroughs have been achieved in the fields of oncogenic signaling inhibition and particularly immune-checkpoint blockade has triggered substantial enthusiasm during the last decade. Antibody-mediated blockade of negative immune-checkpoint molecules (e.g., PD-1/PD-L1, CTLA-4) has been shown to achieve profound responses in several of solid cancers. Unfortunately, these responses only occur in a subset of patients or, after initial therapy response, these tumors eventually relapse. Thus, elucidating the determinants of intrinsic or therapy-induced resistance is the key to improve outcomes and developing new treatment strategies. Several cytokines and growth factors are involved in the tight regulation of either antitumor immunity or immunosuppressive tumor-promoting inflammation within the tumor microenvironment (TME), of which transforming growth factor beta (TGF-β) is of particular importance. This review will therefore summarize the recent progress that has been made in the understanding of how TGF-βblockade may have the capacity to enhance efficacy of immune-checkpoint therapy which presents a rational strategy to sustain the antitumor inflammatory response to improve response rates in tumor patients. Finally, I will conclude with a comprehensive summary of clinical trials in which TGF-βblockade revealed therapeutic benefit for patients by counteracting tumor relapses.

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Urokinase receptor in human malignant mesothelioma cells: role in tumor cell mitogenesis and proteolysis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.268.6.l972 ◽

1995 ◽

Vol 268 (6) ◽

pp. L972-L982 ◽

Cited By ~ 13

Author(s):

S. Shetty ◽

A. Kumar ◽

A. Johnson ◽

S. Pueblitz ◽

S. Idell

Keyword(s):

Molecular Weight ◽

Tumor Cell ◽

Malignant Mesothelioma ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Low Molecular Weight ◽

Metabolic Labeling ◽

Plasminogen Activator Inhibitor 1 ◽

Necrosis Factor Alpha ◽

Amino Terminal

Urokinase (uPA) interacts with its receptor (uPAR) to promote proteolysis and tumor migration, functions of potential importance in the pathogenesis of malignant mesothelioma. Immunohistochemistry of human malignant mesothelioma tissue and mesothelioma cells (MS-1) showed that mesothelioma cells express uPAR. We isolated uPAR from MS-1 cells by metabolic labeling and showed that it could be induced by phorbol myristate acetate (PMA), lipopolysaccharide (LPS), a transforming growth factor-beta (TGF-beta) or tumor necrosis factor-alpha (TNF-alpha). Experiments with MS-1 cells showed that uPA binding was saturable, specific, and reversible with a mean dissociation constant (Kd) of 5.4 +/- 1.1 nM. Binding was inhibited by a blocking antibody to uPAR and by the uPA amino-terminal fragment (ATF), but not by low molecular weight uPA. uPAR expression was regulated transcriptionally and translationally; antisense oligonucleotides blocked expression of uPAR protein. Plasminogen activator inhibitor-1 (PAI-1) inhibited PA activity of preformed uPA/uPAR complexes and increased cycling of the receptor from the cell surface. Stimulation of subconfluent MS-1 cells by high molecular weight or recombinant uPA, but not ATF or low molecular weight fragment, caused concentration-dependent incorporation of [3H]thymidine. These data indicate a novel mechanism by which malignant mesothelioma cells localize pericellular proteolysis and concurrently regulate tumor cell proliferation.

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Growth differentiation factor-15 is associated with age-related monocyte immunosenescence

10.1101/2020.02.05.935643 ◽

2020 ◽

Author(s):

Brandt D. Pence ◽

Johnathan R. Yarbro ◽

Russell S. Emmons

Keyword(s):

Mitochondrial Function ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Immune Cell ◽

Inflammatory Responses ◽

Cell Subset ◽

Cytokine Gene Expression ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Age Related

ABSTRACTBackgroundImmunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses.ResultsMonocyte interleukin-6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF-15 levels. Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity.ConclusionsThe results of these analyses suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus may be an attractive candidate for therapeutic intervention to ameliorate this.

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Ionizing radiation improves RIG-I mediated immunotherapy through enhanced p53 activation in malignant melanoma

10.1101/2021.10.16.464638 ◽

2021 ◽

Author(s):

Silke Lambing ◽

Stefan Holdenrieder ◽

Patrick Müller ◽

Christian Hagen ◽

Stephan Garbe ◽

...

Keyword(s):

Cell Death ◽

Malignant Melanoma ◽

Tumor Cell ◽

Low Dose ◽

Immune Cell ◽

Cytotoxic T Cell ◽

Great Promise ◽

Type I ◽

Tumor Cell Death

The activation of the innate immune receptor RIG-I is a promising approach in immunooncology and currently under investigation in clinical trials. RIG-I agonists elicit a strong immune activation in both tumor and immune cells and induce both direct and indirect immune cell-mediated tumor cell death which involves tumor-specific cytotoxic T-cell response and type I interferon-driven innate cytotoxic immunity. Besides RIG-I, irradiation is known to induce cytotoxic DNA damage resulting in tumor debulking followed by the induction of tumor-specific immunity. To date, it is unclear whether the molecular antitumor effects of RIG-I and irradiation are additive or even synergize. Here, we investigated the combination of RIG-I activation with radiotherapy in melanoma. We found that low dose x-ray irradiation enhanced the extent and immunogenicity of RIG-I mediated tumor cell death in human and murine melanoma cell lines and in the murine B16 melanoma model in vivo. Pathway analysis of transcriptomic data revealed a central role for p53 downstream of the combined treatment, which was corroborated using p53-/- B16 cells. In vivo, the additional effect of irradiation on immune cell activation and inhibition of tumor growth was lost in mice carrying p53-knockout B16 tumors, while the response to RIG-I stimulation in those mice was maintained. Thus, our results identify p53 as pivotal for the synergy of RIG-I with irradiation, resulting in potent induction of immunogenic tumor cell death. Consequently, low dose radiotherapy holds great promise to further improve the efficacy or RIG-I ligands especially in patients with malignant melanoma or other tumors exhibiting a functional p53 pathway.

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Investigation on Potential Correlation Between the RNA-Binding Protein of Evolutionarily Conserved MEX3 Family and Non–Small-Cell Lung Cancer

10.21203/rs.3.rs-800392/v1 ◽

2021 ◽

Author(s):

Ming Zhang ◽

Hualiang Zhang ◽

Linfeng Cao ◽

Gouxin Hou ◽

Chao Lu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Rna Binding ◽

Immune Cell ◽

Tumor Development ◽

Treatment Strategies ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Cell Death

Abstract Background As mRNA binding proteins, MEX3 (muscle excess 3) family highlights its unique characteristics and plays an emerging role in post-transcriptionally regulating programmed of biological processes, including tumor cell death and immunological relevance. These have been shown to be involved in various diseases, however, the role of MEX3 in non-small-cell lung cancer (NSCLC) has not been fully elucidated. Results In this study, we found that the sequence or copy number of MEX3 gene did not change significantly, which can explain the stability of malignant tumor development through the COSMIC database. Further, gene expression in NSCLC was examined using the Oncomine™ database, and the prognostic value of each gene was analyzed by Kaplan-Meier analysis. The results showed that overexpressed of MEX3A, MEX3B, MEX3C and MEX3D were associated with significantly lower OS in patients with NSCLC and LUAD, while overexpressed of MEX3D was associated with significantly poorer OS in patients with LUSC. We also applied the Tumor Immune Estimation Resource (TIMER) tool to assess the correlations between distinct MEX3 and the infiltrating immune cell landscape. Conclusion On this subject, we have learned about the complexity and heterogeneity of NSCLC through MEX3. We found that most of MEX3 is highly expressed in NSCLC. High expression indicates a poor prognosis and has a certain immune correlation. Therefore, these conclusions can lay a framework for the prognosis of NSCLC patients and the development of treatment strategies in the future.

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Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Cancers ◽

10.3390/cancers12051347 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1347 ◽

Cited By ~ 6

Author(s):

Jeffrey Norton ◽

Deshka Foster ◽

Malini Chinta ◽

Ashley Titan ◽

Michael Longaker

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Parenchymal Cell ◽

Surgical Techniques ◽

Treatment Strategies ◽

The United States ◽

Cancer Associated Fibroblasts ◽

Cancer Cell Growth

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

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Abstract 425: Doxorubicin Upregulation of the Fibrotic Transforming Growth Factor-beta Pathway

Circulation Research ◽

10.1161/res.119.suppl_1.425 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Trevi A Ramirez ◽

Greg Aune

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Increased Risk ◽

Pediatric Cancer Patients ◽

Growth Factor Beta ◽

Tgfb Signaling ◽

Old Mice

Childhood cancer survivors are at an increased risk of heart disease as a result of their cancer treatments. Drugs like doxorubicin (DOX) are an effective part of treatment regimens, but have been proven to cause acute and chronic cardiotoxicity (DOX tox). An under-investigated aspect of DOX tox is the interstitial fibrosis that the majority of patients develop. This project aims to better understand the pathology of DOX-induced cardiac fibrosis and the role of the pro-fibrotic transforming growth factor-beta (TGFb) signaling pathway. Research in the area of fibrosis and the effect of DOX on cardiac fibroblasts will increase our understanding of DOX tox. This understanding will allow for improved treatment of pediatric cancer patients by reducing the cardiotoxic sequelae of many standard chemotherapy regimens. Cardiac fibroblasts, isolated from 3 week old mice and treated with 5 μM DOX, showed an increase in nuclear pSMAD compared to control cells via fluorescent immunocytology (2.06 ± 0.26 vs 1.13 ± 0.15, p<0.05). Mice treated with 3 mg/kg DOX injections from 2 weeks to 6 weeks of age showed increased TGFb staining in the left ventricle (1.83 ± 0.34 vs 0.87 ± 0.28, p<0.05) a week after treatment ceased. A subset of mice were followed into old age and sacrificed at 80 weeks. A clear increase in TGFb was seen with age. However, 80 week mice that were exposed to DOX early in life showed a greater increase in TGFb staining compared to untreated 80 week old mice (44.50 ± 2.48 vs 30.93 ± 2.30, p<0.001). Early DOX exposure causes chronic molecular changes as evidenced by acute and chronic changes in signaling molecules in cardiac tissue. Changes in collagen seen in earlier studies and increases in MMP-2 from the literature suggest a cardiac remodeling phenotype in DOX-exposed animals. This project demonstrates that DOX initiates changes to pro-fibrotic pathways, seemingly driven by the TGFb signaling pathway.

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619 Evaluating the effectiveness of targeted ADC therapy in a patient-derived ex vivo tumoroid model, 3D-EX, for quantitative tumor cell killing

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0619 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A655-A655

Author(s):

Jenny Kreahling ◽

Jared Ehrhart ◽

Mibel Pabon ◽

Stephen Iwanowycz ◽

Tina Pastoor ◽

...

Keyword(s):

Cell Death ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Immune Cells ◽

Immune Cell ◽

Confocal Imaging ◽

Tumor Cell Death ◽

Drug Conjugates ◽

Tumor Cell Killing ◽

Antibody Drug

BackgroundAntibody drug conjugates (ADCs) are an effective tool for site directed delivery of cytotoxic agents to cancer cells. Tailoring of ADC-specificity to the uniqueness of a patient‘s tumor can aid in direct-targeting of tumor cells and potentially improve drug responsiveness. Here we evaluate the potential of using an ADC therapy for targeted tumor cell death and immune cell activation in combination with checkpoint inhibitors in 3D tumoroids.MethodsAll human tumor samples were obtained with proper patient consent and IRB approval. Fresh patient tumor tissue of various histologic types including CRC and NSCLC were processed to generate uniform sized live 3D tumoroids measuring 150 µm in size. Treatment groups included a conjugated ADC therapeutic antibody alone or in combination with PD-1/PD-L1 inhibitors. Culture supernatants were collected for multiplex analysis of cytokine release in media. Additionally, flow cytometry was used to assess the activation profile of resident immune cells in combination with high-content confocal imaging to determine extent of tumor cell death in the intact tumor extracellular matrix.ResultsUsing fresh patient-derived tumoroids, we observed ADC-mediated cell death and activation of immune cells within the tumor microenvironment. Production of pro-inflammatory cytokines correlated with increased activation of tumor infiltrating immune cell populations. The improved immune response led to increased tumor cell killing within the 3D tumor microenvironment observed by high-content confocal imaging.ConclusionsIn this study we demonstrate that our physiologically relevant 3D tumoroid model is an effective system to assess novel antibody drug conjugates and to develop rational drug combinations with other immuno-oncology agents. Furthermore, implementation of 3D-EX platform, in the clinical setting, may also allow for determination of the most effective combinatorial immuno-oncology treatment strategies for individualized patient care.Ethics ApprovalThe study was approved by Chesapeake IRB Pro00014313.

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