Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation

Microenvironmental modulation of the developing tumour: an immune-stromal dialogue.

Successful establishment of a tumour relies on a cascade of interactions between cancer cells and stromal cells within an evolving microenvironment. Both immune and nonimmune cellular components are key factors in this process, and the individual players may change their role from tumour elimination to tumour promotion as the microenvironment develops. While the tumour-stroma crosstalk present in an established tumour is well-studied, aspects in the early tumour or premalignant microenvironment have received less attention. This is in part due to the challenges in studying this process in the clinic or in mouse models. Here, we review the key anti- and pro-tumour factors in the early microenvironment and discuss how understanding this process may be exploited in the clinic

Impact of Locally Administered Carboxydextran‐Coated Super‐Paramagnetic Iron Nanoparticles on Cellular Immune Function

Interstitially administered iron oxide particles are currently used for interoperative localization of sentinel lymph nodes (LNs) in cancer staging. Several studies have described concerns regarding the cellular accumulation of iron oxide nanoparticles relating them to phenotype and function deregulation of macrophages, impairing their ability to mount an appropriate immune response once an insult is present. This study aims to address what phenotypic and functional changes occur during lymphatic transit and accumulation of these particles. Data show that 60 nm carboxydextran-coated iron nanoparticles use a noncellular mechanism to reach the draining LNs and that their accumulation in macrophages induces transient phenotypic and functional changes. Nevertheless, macrophages recover their baseline levels of response within 7 days, and are still able to mount an appropriate response to bacterially induced inflammation

Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity

Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid β was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and β-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. Significance This study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid β. We term this novel process “Tumor-induced NETosis” (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome

Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth

Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR(+) macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease.Peer reviewe

Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis.

Tumour-associated macrophages (TAMs) play an important role in tumour progression, which is facilitated by their ability to respond to environmental cues. Here we report, using murine models of breast cancer, that TAMs expressing fibroblast activation protein alpha (FAP) and haem oxygenase-1 (HO-1), which are also found in human breast cancer, represent a macrophage phenotype similar to that observed during the wound healing response. Importantly, the expression of a wound-like cytokine response within the tumour is clinically associated with poor prognosis in a variety of cancers. We show that co-expression of FAP and HO-1 in macrophages results from an innate early regenerative response driven by IL-6, which both directly regulates HO-1 expression and licenses FAP expression in a skin-like collagen-rich environment. We show that tumours can exploit this response to facilitate transendothelial migration and metastatic spread of the disease, which can be pharmacologically targeted using a clinically relevant HO-1 inhibitor

The Vehicle, Fall 1992

Table of Contents DeconstructivismPeter F. Essigpage 5 Homecoming Pep RallyPeter F. Essigpage 6 McAfee GymnasiumWalt Howardpage 7 Morton ParkAnn Moutraypage 9 Why The Willows WeepPeter F. Essigpage 10 UntitledStephen P. Carmodypage 10 A Stranger\u27s MorningBen Hausmannpage 11 deMONSTERative pronounsJoAnna Wolaverpage 12 2.5%Jill S. Pilonpage 13 The BottleStacey Kruegerpage 14 Suppression Jean K. Graypage 15 ProgressStacey Kruegerpage 16 Daily LessonsJennifer Moropage 17 Sunset TheaterMichelle R. Hokepage 20 Eagle GT\u27sJarrod T. Shieldspage 21 New HouseRandy Lisspage 22 UntitledStephen P. Carmodypage 23 Renting Classics on a Saturday NightNancy Jamespage 24 UntitledJacqueline Hallpage 25 Alone While He SleepsSandy Beauchamppage 26 Sand and SeaThomas Schnarrepage 27 loveMichelle R. Hokepage 28 Backward Ass Junkie FunkSandy Beauchamppage 28 These Things You KeepTom McGrathpage 29 Springhill CrestRobert M. Reutherpage 30 The Pass OverLarry Irvinpage 31 The Stolen ChildTom McGrathpage 32 Before the Recycling KickWalt Howardpage 37 Authors\u27 Pagepage 38https://thekeep.eiu.edu/vehicle/1058/thumbnail.jp

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation