Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.Significance:NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799

Carcinoma-associated fibroblasts (CAF) are a potential therapeutic target for both direct and indirect regulation of cancer progression and therapy response. In this issue of Cancer Research, Ford and colleagues investigate the influence of CAF on the immune environment of tumors, specifically focusing on the regulation of CD8+ T cells, required for immune therapy response. Their work suggests a role for stromally expressed NADPH oxidase 4 (NOX4) as a modulator of reactive oxygen species that in turn can reduce the number of CD8+ T cells locally. Inhibition of NOX4 increased CD8+ T cells and restored responsiveness to immune therapy, suggesting an indirect stromally targeted avenue for therapy resensitization.See related article by Ford et al., p. 1846

BACKGROUND AND PURPOSE:

Not all tandem occlusions diagnosed on traditional vascular imaging modalities, such as MRA, represent actual complete ICA occlusion. This study aimed to explore the utility of high-resolution vessel wall imaging in identifying true ICA tandem occlusions and screening patients for their suitability for endovascular recanalization.

BACKGROUND AND PURPOSE:

Flow-diverter treatment for previously stented aneurysms has been reported to be less effective and prone to complications. In this study, we evaluated the effectiveness and safety of flow diverters for recurrent aneurysms after stent-assisted coiling.

BACKGROUND AND PURPOSE:

Computed tomography angiography offers a non-invasive alternative to DSA for the assessment of cerebral vasospasm following subarachnoid hemorrhage but there is limited evidence regarding its reliability. Our aim was to perform a systematic review (Part I) and to assess (Part II) the inter- and intraobserver reliability of CTA in the diagnosis of cerebral vasospasm.

BACKGROUND AND PURPOSE:

It is currently not completely clear how well radiologists perform in evaluating large-vessel occlusion on CTA in acute ischemic stroke. The purpose of this study was to investigate potential factors associated with diagnostic error.

Nắm rõ và tuân theo những nguyên tắc thiết kế nội thất dưới đây sẽ giúp bạn tránh được những sai lầm không đáng có trong quá trình lập kế hoạch và triển khai dự án thiết kế nội thất.

Infographic dưới đây giới thiệu một số nguyên tắc cơ bản trong thiết kế nhà bếp hiện đại, góp phần mang tới sự tiện nghi và cảm giác thoải mái cho người nội trợ.

Hào hứng khi mua nhà lần đầu tiên nhưng vì thiếu kinh nghiệm, chủ quan nên nhiều người đã mắc phải sai lầm đáng tiếc. Để việc mua nhà không gây hối tiếc trong tương lai, hãy đảm bảo bạn không mắc phải 9 sai lầm dưới đây:

Giao dịch bất động sản là quá trình phức tạp, trải qua nhiều công đoạn. Nếu nhà đầu tư không cẩn trọng, rất có thể bị mất sạch vốn do vướng phải những giao dịch bất chính, chụp giật.

Khi mua bán bất động sản, khách hàng cần yêu cầu bên bán cung cấp đầy đủ các giấy tờ để chứng minh pháp lý của bất động sản giao dịch. Các giấy tờ đó là gì? Các bước thực hiện giao dịch ra sao?... sẽ được Batdongsan.com.vn trả lời cụ thể qua infographic dưới đây:

Căn hộ chung cư là loại hình nhà ở nằm trong một dự án gồm nhiều căn hộ, quá trình mua bán, chất lượng bàn giao và việc hoàn thiện đều được thực hiện theo hợp đồng ký với chủ đầu tư. Để giúp người mua chung cư lần đầu không bỡ ngỡ, Batdongsan.com.vn tổng hợp những thông tin chính mà người mua cần tìm hiểu trước khi thực hiện giao dịch như sau:

Không phải ai cũng có đủ điều kiện để mua một ngôi nhà mới nên nhiều người chọn mua nhà cũ để tiết kiệm chi phí. Nếu chưa có kinh nghiệm chọn mua nhà cũ, bạn hãy xem 6 lưu ý dưới đây để chọn được ngôi nhà ưng ý:

Tự làm vườn không chỉ tiết kiệm túi tiền mà còn góp phần bảo vệ hành tinh xanh. Hãy thử tái chế những món đồ bỏ đi ở quanh nhà và tạo nên một khu vườn nhỏ gọn, phong cách, phù hợp với mọi không gian.

It all boils down to how resilient the region is, says an urban planner and designer based in Manila.

The Law on Housing of Vietnam allows foreigners to purchase Vietnam property but with strict conditions and procedures as listed in the following infographic.

We're bringing you something new: SpeakerChat. This event is both a way to revisit some great eLearning Guild content from a recorded session while also […]

The post SpeakerChat for 05/01/20: Rapid Prototyping for Your eLearning Projects appeared first on e-Learning Feeds.

Generative visuals and eerie sound design based on height maps of glaciers, canyons and estuaries. London-based motion graphic designer Sophie Marschner transforms real-world data into a delicate digital topography in Monolith. By using the height maps of various large-scale landmarks, including glaciers, canyons and estuaries, Marschner maps the outside world into a more intimate, digital […]

The post Sophie Marschner turns real-world data into a digital topography in Monolith appeared first on FACT Magazine.

Bamboo is a renewable material that when microwaved becomes stronger by weight than steel or concrete – which could make it ideal for constructing buildings, cars and planes

Not because of public concerns, although there are plenty of those, but because of the pandemic-induced plunge in local real estate.

Today, Anna and Chris get counseled. Phil gets jealous of someone’s fishing skills. Cassandra gets every support conversation. And you, dear listener, get a podcast!

Square Enix comes up with an incredibly innovative idea to make money. Kickstarter proves itself to be the answer to everyone’s needs once again. And...

You won’t get skunked this week with a full-fledged RPGCast! We dissect the recent Nintendo Direct (BOWSER IS TAKING OVER), discuss our Now Playing (with a love-hate CompileHeart relationship), and have a heavy dose of fun feedback.

The Guardian’s fashion editor heads to the stables to find out whether the tranquility of horses can help slow her busy life

One cold, bright morning in January, I stood in a field in Gloucestershire with my eyes closed and imagined I had four legs. Just metres away was a herd of eight horses. Before meeting them, advised therapist Lisanne Peters, it was wise to meditate. First, she told me to focus on sensations – the smell of hay; the birdsong. Then she instructed me to imagine myself, centaur-like, “with another back and another set of legs behind you. Feel how sturdy, how grounded, you are.”

The anti-cancer medicine venetoclax could improve the current therapy for estrogen receptor-positive (ER+) breast cancer, according to preclinical studies. The promising preclinical results for this 'triple therapy' have underpinned a phase 1 clinical trial in Melbourne, Australia, that is combining venetoclax with hormone therapy and CDK4/6 inhibitors in patients with ER+ breast cancer.

The novel coronavirus pandemic has now killed more than 275,000 people worldwide. Over 3.9 million people across the world have been diagnosed with COVID-19, the disease caused by the new respiratory virus, according to data compiled by the Center for Systems Science and Engineering at Johns Hopkins University. The actual numbers are believed to be much higher due to testing shortages, many unreported cases and suspicions that some governments are hiding the scope of their nations' outbreaks.

An analysis of the fossilized teeth of Deinonychus antirrhopus, a species of wolf-sized dromaeosaurid dinosaur that lived between 115 and 108 million years ago (Cretaceous period) in what is now the United States, adds to the growing evidence that this and other raptors were not complex social hunters by modern mammalian standards. The image of [...]

Mercury-nominated UK rapper, Ty, has died aged only 47 after contracting coronavirus.

Tara Reade has claimed in a new interview that Joe Biden used graphic language to proposition her for sex when he allegedly assaulted her in 1993.

Marine biologist Cristina Mittermeier discovered that visual storytelling, rather than data sets, allowed her to be a better advocate for the ocean

Repurposing existing medicines focused on known drug targets is likely to offer a more rapid hope of tackling COVID-19 than developing and manufacturing a vaccine, argue an international team of scientists.

It has a Snapdragon 765G, a headphone jack, water resistance, and wireless charging.

Residents rebelled over plans to collect and use their data, among other things.

Some of the top creative minds at Mexican broadcaster Televisa are puzzling over an unexpected challenge: crafting their signature soap operas without a single love scene, or even a tender kiss.

A man with a 'devil gremlin' tattoo is being sought by police after a teen was dragged into the bushes and raped in south-east London.

Police are searching for a man they wish to speak to following the attempted rape of a woman in north-east London street.

Read our live updates on coronavirus HERE Coronavirus: The symptoms

Coronavirus: the symptoms Read our LIVE updates on coronavirus here

Vivek Sharma was described as a gentle soul who was kind and generous

Prince Charles has warned we are "rapidly destroying" biodiversity across the planet.

Prince Louis has shown his support for the NHS by making a rainbow poster for a series of photographs to mark his second birthday.

Read our live updates on coronavirus HERE Coronavirus: The symptoms

A woman in her 40s was allegedly gang-raped after police quarantined her in a school overnight in India.

Royal Mail has stopped Saturday letter deliveries across the UK until further notice to "ease the additional burden" on staff caused by the coronavirus pandemic.

Police are searching for a man in connection with an alleged rape at Embankment in central London.

London's transport system could be "rapidly overwhelmed" by a surge in passengers needing to keep to social distancing rules after the coronavirus lockdown ends, a briefing to emergency planners has revealed.

Princess Charlotte's fifth birthday has been marked by the release of photographs showing the young royal helping to load a van with food and delivering meals for those in need.

Two brothers who preyed on women leaving bars and nightclubs before carrying out sexual assaults have been convicted.