TP53 Codon 72 Polymorphism Impacts Macrophage Activation through Reactive Oxygen Species-Dependent Cell Signaling Alterations.

The role of the most common TP53 single-nucleotide polymorphism (SNP) at codon 72, which encodes for proline (P72) or arginine (R72), in the regulation of the immune system has not yet been thoroughly explored. We found that this SNP contributes to aggravated inflammatory response in COVID-19 patients resulting from biased macrophage activation. R72-P53 inhibits mitochondrial manganese superoxide dismutase, leading to impaired reactive oxygen species scavenging, oxidation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and, consequently, its inhibition.

Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells.

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy.

Listeria-based immunotherapy directed against CD105 exerts anti-angiogenic and anti-tumor efficacy in renal cell carcinoma.

Targeting tumor-associated angiogenesis is currently at the forefront of renal cell carcinoma (RCC) therapy, with sunitinib and bevacizumab leading to increased survival in patients with metastatic RCC (mRCC). However, resistance often occurs shortly after initiation of therapy, suggesting that targeting the tumor-associated vascular endothelium may not be sufficient to eradicate RCC. This study reports the therapeutic efficacy of a Listeria (Lm)-based vaccine encoding an antigenic fragment of CD105 (Lm-LLO-CD105A) that targets both RCC tumor cells and the tumor-associated vasculature.

Inside-Out of Complement in Cancer.

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity regulation of host cell in the tumor microenvironment.

Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine.

Nanoparticle-based anticancer medications were first approved for cancer treatment almost 2 decades ago. Patients benefit from these approaches because of the targeted-drug delivery and reduced toxicity, however, like other therapies, adverse reactions often limit their use. These reactions are linked to the interactions of nanoparticles with the immune system, including the activation of complement.

The Role of Complement in Angiogenesis.

The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer.

Complement as Prognostic Biomarker and Potential Therapeutic Target in Renal Cell Carcinoma.

Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma.

Therapeutic Targeting of Vasculature in the Premetastatic and Metastatic Niches Reduces Lung Metastasis.

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e.

The Codon 72 Polymorphism Contributes to TSC Tumorigenesis through the Notch-Nodal Axis.

We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of and that R72 increases the risk for angiomyolipoma. R72 transactivates and better than the proline variant of codon 72 (P72); therefore, the expression of and is increased in angiomyolipoma cells that carry R72.

Complementing Cancer Metastasis.

Complement is an effector of innate immunity and a bridge connecting innate immunity and subsequent adaptive immune responses. It is essential for protection against infections and for orchestrating inflammatory responses. Recent studies have also demonstrated contribution of the complement system to several homeostatic processes that are traditionally not considered to be involved in immunity.

Targeting complement-mediated immunoregulation for cancer immunotherapy.

Complement was initially discovered as an assembly of plasma proteins "complementing" the cytolytic activity of antibodies. However, our current knowledge places this complex system of several plasma proteins, receptors, and regulators in the center of innate immunity as a bridge between the initial innate responses and adaptive immune reactions. Consequently, complement appears to be pivotal for elimination of pathogens, not only as an early response defense, but by directing the subsequent adaptive immune response.

Notch transactivates Rheb to maintain the multipotency of TSC-null cells.

Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event.

The Ribosomal Protein S19 Suppresses Antitumor Immune Responses via the Complement C5a Receptor 1.

Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors.

Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs.

In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor-mediated proliferation but not through recruitment from the circulation.

Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche.

The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGFβ and IL10 production in these cells.

Antitumor activity of a monoclonal antibody targeting major histocompatibility complex class I-Her2 peptide complexes.

Background: Applications of trastuzumab are limited to breast cancer patients with high Her2-expressing tumors. We developed a T-cell receptor mimic (TCRm) monoclonal antibody (hereafter called RL1B) that targets the Her2-E75 peptide (residues 369-377)-HLA-A2 complex and examined its effects in Her2-expressing cancer cells.

Methods: RL1B binding affinity was determined by surface plasmon resonance and specificity was demonstrated using Her2 antigen-positive and negative tumor cell lines.

A complement-IL-4 regulatory circuit controls liver regeneration.

The involvement of IL-4 in liver regeneration has not yet been recognized. In this article, we show that IL-4, produced by NKT cells that accumulate in regenerating livers after partial hepatectomy, contributes to this process by regulating the activation of complement after liver resection in mice. The mechanism of this regulation was associated with the maintenance of an appropriate level of IgM in mouse blood, because IgM deposited in liver parenchyma most likely initiated complement activation during liver regeneration.

Absence of mannose-binding lectin prevents hyperglycemic cardiovascular complications.

Diabetes, stress, pharmaceuticals, surgery, and physical trauma can lead to hyperglycemic conditions. A consistent relationship has been found between chronic inflammation and the cardiovascular complications of hyperglycemia. We hypothesized that cardiomyopathy and vasculopathy resulting from acute hyperglycemia are dependent on mannose-binding lectin (MBL) and lectin complement pathway activation.

TCR mimic monoclonal antibodies induce apoptosis of tumor cells via immune effector-independent mechanisms.

mAbs that recognize peptides presented on the cell surface by MHC class I molecules are potential therapeutic agents for cancer therapy. We have previously demonstrated that these Abs, which we termed TCR mimic mAbs (TCRm), reduce tumor growth in models of breast carcinoma. However, mechanisms of TCRm-mediated tumor growth reduction remain largely unknown.

Early post-operative measurement of cytokine plasma levels combined with pre-operative bilirubin levels identify high-risk patients after liver resection.

Identification of patients at risk of a complicated course after liver resection is crucial for adapting post-operative care. In the present study, we investigated the diagnostic value of the plasma levels of various cytokines obtained immediately after surgery. IL-6, IL-10, IL-8, monokine induced by interferon-γ (MIG), monocyte chemotactic protein-1 (MCP-1) and interferon-inducible protein-10 (IP-10) concentrations were measured in 26 patients after liver resection using a cytometric bead assay and were correlated with liver function, resectate weight, surgery duration, ischemia/reperfusion, hospitalization time and occurrence of complications.