scholarly journals Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 960
Author(s):  
Tiziana Cotechini ◽  
Aline Atallah ◽  
Arielle Grossman
Keyword(s):  
Tumor Progression ◽  
Therapeutic Potential ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Reduce Tumor Burden ◽  
Tumor Growth And Metastasis ◽  
Macrophage Populations ◽  
Cancer Agent ◽  
Metastatic Sites ◽  
And Function

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.

Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Siyu Tan ◽  
Xiaowei Guo ◽  
Mengzhen Li ◽  
Tixiao Wang ◽  
Zehua Wang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Negative Regulator ◽  
Cell Maturation ◽  
Downstream Target ◽  
Conditional Deletion ◽  
Inhibition Of Tumor Growth ◽  
Tumor Growth And Metastasis ◽  
And Function

The maturation and functional competence of natural killer (NK) cells is a tightly controlled process that relies on transcription factors (TFs). Here, we identify transcriptional repressor zinc fingers and homeoboxes 2 (Zhx2) as a novel regulator that restricts NK cell maturation and function. Mice with Zhx2 conditional deletion in NK cells (Zhx2Δ/Δ) showed accumulation of matured NK cells. Loss of Zhx2 enhanced NK cell survival and NK cell response to IL-15. Transcriptomic analysis revealed Zeb2, a key TF in NK cell terminal maturation, as a direct downstream target of Zhx2. Therapeutically, transfer of Zhx2-deficient NK cells resulted in inhibition of tumor growth and metastasis in different murine models. Our findings collectively unmask a previously unrecognized role of Zhx2 as a novel negative regulator in NK cell maturation and highlight its therapeutic potential as a promising strategy to enhance NK cell–mediated tumor surveillance.

scholarly journals Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Sunish Mohanan ◽  
Brian D. Cherrington ◽  
Sachi Horibata ◽  
John L. McElwee ◽  
Paul R. Thompson ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Progression ◽  
Cell Lines ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Multiple Tumor ◽  
Cancer Pathogenesis ◽  
Specific Distribution ◽  
And Function

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1–4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.

scholarly journals Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity

2021 ◽  
Vol 118 (26) ◽  
pp. e2107424118
Author(s):  
Itziar Ibarlucea-Benitez ◽  
Polina Weitzenfeld ◽  
Patrick Smith ◽  
Jeffrey V. Ravetch
Keyword(s):  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Tumor Burden ◽  
Immune Checkpoints ◽  
Reduce Tumor Burden ◽  
The Impact

Given the role of myeloid cells in T cell activation and in the antitumor response, targeting checkpoint molecules expressed on this population represents a promising strategy to augment antitumor immunity. However, myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting the myeloid receptors Siglec-7 and Siglec-9 in vivo. By using a humanized immunocompetent murine model, we demonstrate that human Siglec-7 and Siglec-9, in addition to the murine homolog Siglec-E, inhibit the endogenous antitumor immune response, as well as the response to tumor-targeting and immune checkpoint inhibiting antibodies in vivo. The impact of these Siglecs on tumor progression is highly dependent on the anatomical distribution of the tumor and, as a consequence, the local tumor microenvironment, as tumors with a more immune-suppressive tumor microenvironment are less sensitive to Siglec perturbation. Finally, to assess the potential of these two receptors as targets for immunotherapy, we developed Fc engineered blocking antibodies to Siglec-7 and Siglec-9 and demonstrate that Siglec-7 and Siglec-9 blockade can significantly reduce tumor burden in vivo, demonstrating the therapeutic potential of targeting these two receptors.

Effect of the orally available MET inhibitor PF-2341066 on tumor burden and metastasis in an orthotopic xenograft model of bladder cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 263-263
Author(s):  
M. Sorbellini ◽  
A. Giubellino ◽  
G. Srivastava ◽  
C. Sourbier ◽  
P. A. Pinto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transitional Cell ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model ◽  
Reduce Tumor Burden ◽  
Met Inhibitor ◽  
Metastatic Sites ◽  
Nih 3T3

263 Background: Met over-expression has been found in bladder cancer (CaB). However, to date, the effects of Met inhibition in CaB have not been reported. We used a small, orally available, highly specific Met-inhibitor currently on phase 2 clinical trials, to assess its effects in an orthotopic xenograft model of bladder transitional cell carcinoma (TCC). Methods: An orthotopic xenograft murine model of TCC of the bladder was developed with T24-Luciferase positive bladder cancer cells. NIH 3T3 cells producing human hepatocyte growth factor (hHGF) were implanted subcutaneously in mice to provide a source of hHGF. Animals were treated with the selective Met inhibitor (PF-2341066) intra-peritoneally after positive detection of bladder tumor primary and/or metatastatic disease. Fluorescence imaging (Xenogen IVIS) of mice was performed weekly. Mice were euthanized 4 weeks after the start of treatment and their tissues studied histologically. Results: PF-2341066 was found to reduce tumor burden to below detectable levels in both primary and metastatic sites in all mice treated. No noticeable side effects were detected in treated mice secondary to drug administration. Conclusions: This study is the first to test a small orally available Met-selective inhibitor in an orthotopic, HGF-driven model of human CaB. Our results demonstrate that Met-inhibition by PF-2341066 reduces TCC tumor burden supporting its potential use in patients with bladder cancer. No significant financial relationships to disclose.

Apigenin Alleviates Renal Fibroblast Activation through AMPK and ERK Signaling Pathways In Vitro

2020 ◽  
Vol 21 (11) ◽  
pp. 1107-1118
Author(s):  
Ningning Li ◽  
Zhan Wang ◽  
Tao Sun ◽  
Yanfei Lei ◽  
Xianghua Liu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Protective Role ◽  
Fibroblast Proliferation ◽  
Fibroblast Activation ◽  
And Function ◽  
Activated Fibroblasts ◽  
Tgf Β1

Objective: Renal fibrosis is a common pathway leading to the progression of chronic kidney disease. Activated fibroblasts contribute remarkably to the development of renal fibrosis. Although apigenin has been demonstrated to play a protective role from fibrotic diseases, its pharmacological effect on renal fibroblast activation remains largely unknown. Materials and Methods: Here, we examined the functional role of apigenin in the activation of renal fibroblasts response to transforming growth factor (TGF)-β1 and its potential mechanisms. Cultured renal fibroblasts (NRK-49F) were exposed to apigenin (1, 5, 10 and 20 μM), followed by the stimulation of TGF-β1 (2 ng/mL) for 24 h. The markers of fibroblast activation were determined. In order to confirm the anti-fibrosis effect of apigenin, the expression of fibrosis-associated genes in renal fibroblasts was assessed. As a consequence, apigenin alleviated fibroblast proliferation and fibroblastmyofibroblast differentiation induced by TGF-β1. Result: Notably, apigenin significantly inhibited the fibrosis-associated genes expression in renal fibroblasts. Moreover, apigenin treatment significantly increased the phosphorylation of AMP-activated protein kinase (AMPK). Apigenin treatment also obviously reduced TGF-β1 induced phosphorylation of ERK1/2 but not Smad2/3, p38 and JNK MAPK in renal fibroblasts. Conclusion: In a summary, these results indicate that apigenin inhibits renal fibroblast proliferation, differentiation and function by AMPK activation and reduced ERK1/2 phosphorylation, suggesting it could be an attractive therapeutic potential for the treatment of renal fibrosis.

Strategies for Oral Delivery of Metal-Saturated Lactoferrin

2019 ◽  
Vol 20 (11) ◽  
pp. 1046-1051 ◽  
Author(s):  
Przemysław Gajda-Morszewski ◽  
Klaudyna Śpiewak-Wojtyła ◽  
Maria Oszajca ◽  
Małgorzata Brindell
Keyword(s):  
Biological Activity ◽  
Oral Delivery ◽  
Therapeutic Potential ◽  
Structure And Function ◽  
The Difference ◽  
And Function ◽  
First Time

Lactoferrin was isolated and purified for the first time over 50-years ago. Since then, extensive studies on the structure and function of this protein have been performed and the research is still being continued. In this mini-review we focus on presenting recent scientific efforts towards the elucidation of the role and therapeutic potential of lactoferrin saturated with iron(III) or manganese(III) ions. The difference in biological activity of metal-saturated lactoferrin vs. the unmetalated one is emphasized. The strategies for oral delivery of lactoferrin, are also reviewed, with particular attention to the metalated protein.

scholarly journals Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 726
Author(s):  
Christopher Groth ◽  
Ludovica Arpinati ◽  
Merav E. Shaul ◽  
Nina Winkler ◽  
Klara Diester ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Receptor Expression ◽  
Myeloid Derived Suppressor Cells ◽  
Melanoma Progression ◽  
Relative Contribution ◽  
Immunosuppressive Tumor Microenvironment ◽  
Metastatic Sites

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

scholarly journals Duration of response after DEB-TACE compared to lipiodol-TACE in HCC-naïve patients: a propensity score matching analysis

2021 ◽  
Author(s):  
Irene Bargellini ◽  
Valentina Lorenzoni ◽  
Giulia Lorenzoni ◽  
Paola Scalise ◽  
Gianni Andreozzi ◽  
...  
Keyword(s):  
Propensity Score ◽  
Tumor Progression ◽  
Tumor Response ◽  
Complete Response ◽  
Tumor Burden ◽  
Local Tumor Control ◽  
Lower Number ◽  
Tumor Control ◽  
Duration Of Response

Abstract Objectives To retrospectively compare long-term outcomes of first-line drug-eluting particle (DEB)- transarterial chemoembolization (TACE) and lipiodol-TACE, in patients with unresectable hepatocellular (HCC). Methods We retrospectively reviewed our database to identify adult patients with treatment-naïve unresectable HCC, who underwent TACE from 2006 to 2013. Patients were excluded in the absence of complete medical records relative to first TACE, 1-month follow-up, and/or sufficient follow-up data. Periprocedural complications, duration of hospitalization, 1-month tumor response by mRECIST, time to tumor progression (TTP) and target tumor progression (TTTP), and overall survival (OS) were evaluated. Results Out of an initial series of 656 patients, 329 patients were excluded for unavailability of sufficient baseline and/or follow-up data. The remaining 327 patients underwent either lipiodol-TACE (n = 160) or DEB-TACE (n = 167). Patients treated with lipiodol-TACE had a significantly higher tumor burden. By propensity score, patients were matched according to baseline differences (BCLC stage, uninodular or multinodular HCC, and unilobar or bilobar HCC), resulting in 101 patients in each treatment group. Lipiodol-TACE was associated with a significantly higher incidence of adverse events (p = 0.03), and longer hospitalization (mean, 2.5 days vs 1.9 days; p = 0.03), while tumor response, TTP, and OS were comparable. In patients achieving 1-month complete response (CR) of target tumor, TTTP was significantly (p = 0.009) longer after DEB-TACE compared to lipiodol-TACE (median, 835 vs 353 days), resulting in a lower number of re-treatments during the entire follow-up (0.75 vs 1.6, p = 0.01). Conclusion Compared to lipiodol-TACE, DEB-TACE offers higher tolerability, reduced hospitalization, and more durable target tumor response after CR. Key Points • Compared to lipiodol-TACE, DEB-TACE is better tolerated and has reduced side effects, which translates into shorter hospitalization. • When complete radiological response according to the mRECIST is obtained 1 month after the procedure, DEB-TACE offers a more durable local tumor control compared to lipiodol-TACE. • In these patients, the longer duration of response after DEB-TACE translates into a lower number of re-interventions.

scholarly journals The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

2021 ◽  
Vol 22 (15) ◽  
pp. 7923
Author(s):  
Santiago Alvarez-Argote ◽  
Caitlin C. O’Meara
Keyword(s):  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Normal Function ◽  
Cardiac Conduction ◽  
Cell Detection ◽  
Fate Mapping ◽  
The Novel ◽  
Functional Roles ◽  
Macrophage Populations ◽  
And Function

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

scholarly journals The state of PRRT and its sequencing amongst current therapeutic options for gastroenteropancreatic neuroendocrine tumors

2021 ◽  
Author(s):  
Lauren M Raymond ◽  
Tetiana Korzun ◽  
Adel Kardosh ◽  
Kenneth J. Kolbeck ◽  
Rodney Pommier ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Standard Dose ◽  
Peptide Receptor Radionuclide Therapy ◽  
Somatostatin Analogues ◽  
Tumor Burden ◽  
Treatment Modalities ◽  
Its Sequencing ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Reduce Tumor Burden ◽  
Spectrum Of Patients

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs, however, this may change with emerging data to suggest PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogues, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

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