Deconstructing tumor heterogeneity: The stromal perspective

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportiv

The safety and efficacy of systemic delivery of a new liver-de-targeted TGFβ signaling inhibiting adenovirus in an immunocompetent triple negative mouse mammary tumor model

Aberrant TGFβ signaling is linked to metastasis and tumor immune escape of many cancers including metastatic triple negative breast cancer (mTNBC). Previously, we have found that oncolytic adenoviruses expressing a TGFβ signaling inhibitory protein (sTGFβRIIFc) induced immune activation in a mouse TNBC (4T1) immunocompetent subcutaneous model with intratumoral injection. Systemic administration of adenoviruses can be a superior route to treat mTNBC but faces the challenges of increased toxicity and viral clearance. Thus, we created a liver-de-targeted sTGFβRIIFc- and LyP-1 peptide-expressing adenovirus (mHAdLyp.sT) with enhanced breast cancer cell tropism. Its safety and immune response features were profiled in the 4T1 model. Our data showed that the systemic administration of mHAdLyp.sT resulted in reduced hepatic and systemic toxicity. mHAdLyp.sT was also effective in increasing Th1 cytokines and anti-tumor cell populations by cytokine analysis, spleen/tumor qRT-PCR, and flow cytometry. We further tested the therapeutic effects of mHAdLyp.sT alone and in combination with immune checkpoint inhibitors (ICIs). mHAdLyp.sT alone and with all ICI combinations elicited significant inhibition of lung metastasis by histological analysis. When mHAdLyp.sT was combined with both anti-PD-1 and anti-CTLA-4 antibodies, primary 4T1 tumor growth was also significantly inhibited. We are confident in advancing this new treatment option for mTNBC

Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer

Cholesterol accumulates in prostate lesions and has been linked to prostate cancer (PCa) incidence and progression. However, how accumulated cholesterol contributes to PCa development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared to normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, PCa cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical co-regulators that influence AR activity

Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFα in Castration-Resistant Prostate Cancer

Cholesterol sulfotransferase, SULT2B1b, has been demonstrated to modulate both androgen receptor activity and cell growth properties. However, the mechanism(s) by which SULT2B1b alters these properties within prostate cancer cells has not been described. Furthermore, specific advantages of SULT2B1b expression in prostate cancer cells is not understood. In these studies, single-cell mRNA sequencing (scRNA-seq) was conducted to compare the transcriptomes of SULT2B1b knockdown (KD) versus Control KD LNCaP cells. Over 2,000 differentially expressed (DE) genes were identified along with alterations in numerous canonical pathways, including the death receptor signaling pathway. The studies herein demonstrate that SULT2B1b KD increases tumor necrosis factor alpha (TNF) expression in prostate cancer cells and results in NF-κB activation in a TNF-dependent manner. More importantly, SULT2B1b KD significantly enhances TNF-mediated apoptosis in both TNF-sensitive LNCaP cells and TNF-resistant C4–2 cells. Overexpression of SULT2B1b in LNCaP cells also decreases sensitivity to TNF-mediated cell death, suggesting that SULT2B1b modulates pathways dictating the TNF sensitivity capacity of prostate cancer cells. Probing human prostate cancer patient datasets further support this work by providing evidence that SULT2B1b expression is inversely correlated with TNF-related genes, including TNF, CD40LG, FADD, and NFKB1. Together, these data provide evidence that SULT2B1b expression in prostate cancer cells enhances resistance to TNF and may provide a growth advantage. In addition, targeting SULT2B1b may induce an enhanced therapeutic response to TNF treatment in advanced prostate cancer

Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs

Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME. This FRβ+ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8+ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRβ as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors

Deconstructing tumor heterogeneity: the stromal perspective.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field

Vidareutveckling av SAFOR : En utredning av ramverket SAFOR för operationell risk inom banker

Operationell risk inom banksektorn är ett område under utveckling. Utredningen har behandlat ett ramverk för hantering av operationell risk kallat A Systemic Approach Framework for Operational Risk (SAFOR). Syftet har varit att konkretisera detta ramverk och inom detta utvärdera en metod kallad Damage Evaluation and Effective Prevention (DEEP-metoden) i kombination med ett datoriserat beslutsverktyg benämnt DecideIT. SAFOR hanterar operationell risk som är nära kopplat till företagets processer, personer och system. Dess utformning grundar sig i general system theory, en holistisk verksamhetssyn som minskar risken för överlappning mellan olika riskhanteringsområden. Ramverket är uppde-lat i fyra moduler som hanterar identifiering av risker och riskhanter-ingsstruktur, värdering av olika handlingsalternativ, hantering av riskmått och intervalluppskattningar. DEEP-metoden hanterar identifie-ring av risksituationen och rangordning av olika framtidscenarier. Beslutsverktyget DecideIT är en implementering av DELTA metoden som hanterar intervallskattningar av sannolikheter och värden tillsammans med känslighetsanalyser. Utredningen har genomförts genom litteratur-studie och eget test. Resultatet visar en ökning av ramverkets tillämp-barhet genom införandet av ett processperspektiv där en kartläggning av arbetsflödet visar att DEEP-metoden berör flera moduler inom ramverket. Vid närmare beaktan av ramverkets osäkerhetsmodul klargörs dess syfte till rangordning av alternativ för beslutstagande. Metod och beslutsverktyg inom osäkerhetsmodulen bör hantera osäker-heter, framtidscenarier och vara lättanvänt. Detta visar sig stämma för DEEP-metoden och DecideIT när tillämpbarhetstest utförs. SAFOR anses fungera som grund för helhetsförståelse. Ramverket kan sedan implementeras genom för verksamheten passande metod vilket ökar flexibiliteten mot olika typer av organisationer. Målen för studien anses vara uppfyllda. Fortsatt arbete finns i utformning av tydligare avgräns-ning mellan ramverkets moduler och testning av metoder inom dessa. The investigation deals with a framework named A Systemic Approach Framework for Operational Risk (SAFOR). The aim is to concretize SAFOR and Evaluate the proposed method of Damage Evaluation and Effective Prevention (DEEP) in combination with the decision tool DecideIT. SAFOR deals with operational risk which is linked to the company's processes, people and systems. The framework is based on a holistic approach, which reduces overlap in risk management and consists of four modules which deal with; identification of risk and risk manage-ment structure, risk-reducing alternatives, risk measurement and interval estimates. The DEEP-method handles Identification of risk and Evalua-tion of future scenarios. DecideIT implements the DELTA-method which handles interval assessments for probabilities and values together with Sensitivity Analysis. The investigation was by Literature Studies and a test. A process perspective is proposed to increase the applicability of SAFOR. It discovered that the DEEP-method intersects the framework´s modules. Investigation of the framework´s uncertainty module reveals its aim to sort decision alternatives and that the method and decision tool applied in it should deal with uncertainties, future scenarios and be easy to use. This proved to be true for the DEEP-method and DecideIT by a test. SAFOR is suited to be a source for understanding the whole-ness and various methods can be implemented inside the framework to increase flexibility. The objective of the study is achieved but there is a need for further effort with interfaces and Testing methods within the framework.

2021 CSB/SJU Social Entrepreneur of the Year- Kurt Vickman SJU \u2794 - Founder of the Good Grocer

2021 CSB/SJU Social Entrepreneur of the Year- Kurt Vickman SJU \u2794 - Founder of the Good Groce