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. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.
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., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1β and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes–based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.
There is increased scientific evidence that plants possess a vast and complex arsenal of active ingredients which have the ability to calm or smooth the skin as well as restore actively, heal and protect the skin. The present work deals with the development and evaluation of the poly herbal lotion containing Trigonella foenum-graecum, Citrus lemon, Matricaria chamomilla and Cymbopogon citrates. Different types of formulations oil in water (O/W) herbal lotions namely F1 to F13 were formulated by incorporating different concentrations of stearic acid and Triethanolamine. Formulation of Triethanolamine and stearic acid was optimized as 2.52:9.35. The prepared lotion was evaluated for its antimicrobial, antioxidant and pharmaceutical parameters. The lotion formulation showed no redness, edema, inflammation and irritation during sensitivity test indication that it is safe to use. Stability studies of the lotion showed that the lotion was stable after three months.
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. Lm-LLO-CD105A treatment reduced primary tumor growth in both subcutaneous and orthotopic models of murine RCC. The vaccine conferred anti-tumor immunity and remodeled the tumor microenvironment (TME), resulting in increased infiltration of polyfunctional CD8+ and CD4+ T cells and reduced infiltration of immunosuppressive cell types within the TME. We further provide evidence that the therapeutic efficacy of Lm-LLO-CD105A is mediated by CD8+ T cells and is dependent on the robust antigenic expression of CD105 by RCC tumor cells. The result from this study demonstrates the safety and promising therapeutic efficacy of targeting RCC-associated CD105 expression with Lm-based immunotherapy.
This research evaluated the impact of novel somatostatin receptor subtype‐4 (SSTR4) agonist SM‐I‐26 on microglia inflammatory activation. SSTR4 shows particular promise as a treatment target for Alzheimer's disease (AD) given its microglia and neuronal localization in the brain. A hallmark of AD progression is microgliosis, associated with inflammatory activation. A SSTR4 agonist that lessens microglial inflammatory activity could help mitigate AD progression.The selective and high affinity SSTR4 agonist SM‐I‐26 (Ki: 12nM, EC50: 17nM) was evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS) treatment. After plating for 24hrs, cells were treated for 24hrs with SM‐I‐26 (0, 10, 1000nM) against LPS (0, 10, 100ng/mL). Nitrite (surrogate of nitric oxide, Griess assay) output in media and mRNA expression (RT‐qPCR) from cells of key inflammatory species (Tnf‐α, Il‐6, Il‐1β) were measured. Two‐way ANOVAs with Tukey post‐hoc tests were used to determine significance (α= 0.05).A significant interaction between LPS and SM‐I‐26 (p<0.0001) was found on mean nitrite. Within no LPS, mean nitrite was similar across all concentrations of SM‐I‐26. Within 10 ng/ml LPS, a trend was found with decreased nitrite with 10 and 1000 nM SM‐I‐26 compared to vehicle. Within 100 ng/ml LPS, both 10 and 1000 nM SM‐I‐26 significantly decreased nitrite compared to vehicle control (p<0.0001).Significant interactions were found between SM‐I‐26 and LPS on the mean ddcts of Tnf‐α (p<0.0001) and Il‐β, (p<0.0001). At 0 and 10 ng/mL LPS, 1000 nM SM‐I‐26 significantly increased the mean ddct of Tnf‐α compared to their vehicle controls (p<0.0001). Within 100 ng/ml LPS, SM‐I‐26 dose‐dependently increased the mean ddct for Tnf‐α (10 nM: p= 0.0067, 1000nM: p<0.0001, Tukey) compared to vehicle. These results indicate that 1000 nM SM‐I‐26 significantly decreased Tnf‐α mRNA expression under inflammatory conditions. For Il‐1β, the mean ddcts were similar across all concentrations of SM‐I‐26 with no LPS. At 100 ng/ml LPS, 10 nM and 1000 nM SM‐I‐26 significantly increased the mean ddcts for Il‐β (p<0.0001, and p=0.0040, respectively), indicating these concentrations of SM‐I‐26 decreased Il‐1β mRNA expression with inflammation. For Il‐6, LPS (p<0.0001) and SM‐I‐26 (p<0.0001), but not their interaction (p=0.1106) significantly impacted the mean ddct. SM‐I‐26 at 10 and 1000 nM significantly increased the mean ddct of Il‐6 compared to no SM‐I‐26 (p<0.0001 and p=0.0009, respectively), indicating that SM‐I‐26 decreased Il‐6 mRNA expression.These results show treatment with SM‐I‐26 significantly decreased Tnf‐α, Il‐6, and Il‐1β mRNA expression and mean nitrite levels with increasing LPS inflammatory stimulation. These results support the use of SSTR4 agonists for the mitigation of microglial activation, which could help in the treatment of AD progression.Support or Funding InformationThis work is supported by the National Institutes of Health, National Institute of Aging (R01AG047858)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sigma receptor 1 (Sig1R) and 2 (Sig2R) are expressed in central nervous system, in neurons and microglia. Modulation of these receptors has been identified for the treatment of inflammatory and neurodegenerative disorders, including Alzheimer's disease (AD). This research evaluated the impact of BBZI, a novel pan‐selective Sig1R‐Sig2R ligand in mouse models of Alzheimer's disease and microglia activation.BBZI has high affinity Sig1R‐Sig2R (Sig1R: Ki=0.8nM; Sig2R: Ki=2.5nM), with 100‐fold selectivity over a panel of 30 other receptors. Twelve‐month old Senescence Accelerated Mouse Prone‐8 (SAMP8) and 3xTg AD mice were treated with BBZI (i.c.v.) across a dosing range (0, 0.001, 0.01, 0.1, 1.0μg), and assessed for memory response via T‐maze. BBZI was also evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS). After plating for 24hrs, cells were treated for 24hrs with BBZI (0, 10, 100, 1000nM) against LPS (0, 10, 100ng/mL). Alamar Blue (cellular proliferation) and nitrite (surrogate of nitric oxide) output in media.BBZI significantly enhanced memory in SAMP8 mice at both 0.001μg and 0.01μg doses (p<0.01), and in 3xTg mice at 0.01μg dose (p<0.05), compared to vehicle controls. The mean percent reduction of alamar blue decreased with increasing concentrations of BBZI (p<0.05). The mean percent reduction of alamar blue was significantly lower for 1000nM BBZI compared to 0nM BBZI (p<0.05). No significant difference in nitrite level was observed with increasing concentrations of BBZI (p=0.65).These results identify pan‐selective Sig1R‐Sig2R ligand capacity to enhance memory in two age mouse models of AD, with further capacity to impact of microglial proliferation. Such a pan‐selective ligand shows viability for treatment of cognitive and neurodegenerative conditions.Support or Funding InformationThis work was supported by the School of Pharmacy, Southern Illinois University Edwardsville.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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