![]() Warming: It is important to point out that, emptying the Trash will instantly wipe off Hotel Dash 2: Lost Luxuries 1.0 as well as other files you’ve thrown into the Trash, and that this act is irrevocable, so make sure you haven’t mistakenly deleted anything before emptying the Trash. ![]() In any case you cannot move Hotel Dash 2: Lost Luxuries 1.0 to the Trash or empty the Trash, try holding the Option key as you choose Empty Trash from the Finder menu, or reboot your Mac and try it again later. Some apps installed using the Mac package installer will prompt you for a password when you try to move it to the Trash. Most 3rd party apps can be smoothly uninstalled in that way, but you cannot delete built-in apps by doing this. This drag-to-delete method works in all versions of Mac OS X. Right click the Trash icon and select Empty Trash option to start the uninstall.Drag Hotel Dash 2: Lost Luxuries 1.0 to the Trash (or right click on it and then select Move to Trash option).Open up the Finder, click Applications on the left side, and then select Hotel Dash 2: Lost Luxuries 1.0.Option 1: Drag Hotel Dash 2: Lost Luxuries 1.0 icon to the Trash If Hotel Dash 2: Lost Luxuries 1.0 cannot be quit normally, you can select the app in Activity Monitor, click the large red “Quit Process” button in the left corner and click Force Quit button in the pop-up dialog. To deactivate an app, right click its icon in the dock and select Quit option (or choose Hotel Dash 2: Lost Luxuries 1.0 > Quit Hotel Dash 2: Lost Luxuries 1.0 on the Menu bar).Īlso, you can access the Activity Monitor (located in /Applications/Utilities/ folder), and see if there is any background process pertaining to the app. Prior to the removal of Hotel Dash 2: Lost Luxuries 1.0, you should first log into your Mac with an administrator account, and turn Hotel Dash 2: Lost Luxuries 1.0 off if it is running. In this post we will discuss the following questions: (1) What is the correct way to uninstall Hotel Dash 2: Lost Luxuries 1.0? (2) How to ensure all its accompanying components are removed safely? And (3) is there a shortcut for both Mac novices and experts to take to accomplish Hotel Dash 2: Lost Luxuries 1.0 removal effortlessly? Conventional Steps to Uninstall Hotel Dash 2: Lost Luxuries 1.0 for Mac Even for the experienced users, they may also get lost when trying to uninstall a problematic, stubborn or even malicious application. In the latter case it is quite necessary to clean out those junk files from your Mac for complete removal.įor some novice users, they may have no idea how to remove Hotel Dash 2: Lost Luxuries 1.0 in a proper way. These vestiges can be very small in size, thus leaving them alone may not affect your Mac performance, yet they can also be a large chunks of useless files that occupy a large portion of your hard drive space. However, a fact is often neglected that, even the stand-alone software may might still leave its configuration and preferences files on multiple system directories after you carry out a basic uninstall. Generally speaking, most Mac applications are separate bundles that contain the executable and any associated resources for the app, and therefore users can easily remove any unwanted software (if they are installed properly) from their Macs. In normal cases Mac users just need to simply drag and drop the target app to the Trash and then empty the Trash to perform the standard uninstallation. Uninstalling applications in macOS/Mac OS X is quite different from that in Windows operating system. Things you should know about Mac app removal: How to uninstall Hotel Dash 2: Lost Luxuries 1.0 on Mac computer? If you encounter problem when trying to delete Hotel Dash 2: Lost Luxuries 1.0 as well as its associated components, read through this removal tutorial and learn about how to perfectly remove any unwanted applications on your Mac. How Can I Uninstall Hotel Dash 2: Lost Luxuries 1.0 from My Mac
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This let’s you bring the lenses as close to your eyes as comfortable, allowing you to maximize your field of view it also makes the headset easier to adjust for glasses. Index is one of the only headsets that offers an eye-relief adjustment. Things to love about Index are its excellent tracking performance, wide field of view, quality controllers, great audio, and range of ergonomic adjustments that make it easy to dial in a comfortable and clear fit. That’s why we called it “the enthusiast’s choice” in our full review of the headset. It’s pricey compared to the rest, but has an excellent balance of quality, performance, and comfort. If you’re looking for the very best overall PC VR headset, Valve Index is our pick. The Best Overall: Valve Index – $1,000 Image courtesy Valve See this article for the specs your PC needs to handle VR headsets. Of course, you’ll need a reasonably powerful gaming PC to plug your headset into. PC VR is where you’ll find the highest quality visuals and the most ambitious VR games like Half-Life: Alyx. Quest Pro will be Meta’s first headset to offer face-tracking.Best PC VR headsets | Best standalone VR headsets | Best console VR headsets The Best PC VR Headsets in 2022 To this end, Meta is researching photorealistic codec avatars, but they are still very costly to produce and compute.Ī first step in this direction is VR headsets that can read the facial expressions of VR users in real-time and transfer them to virtual reality. The company wants people to one day meet in virtual spaces and feel as if they are present in the same room. This technology is still far from being ready for the market, as Metas research shows.Ĭo-presence and metaverse telephony are Meta’s ultimate goals. This could be made possible by inward-facing sensors and an external (light field) display. In the reverse case, which Meta calls “ Reverse Passthrough,” outsiders see the eyes and faces of VR users and can thus make eye contact or read facial expressions. To this end, Meta is researching AI-assisted gaze synthesis that generates perspective-correct viewpoints in real-time and with high visual fidelity. One of the problems yet to be solved is that the passthrough technology captures a perspective of the world that is spatially displaced from the eyes, which can be irritating during prolonged use. However, this does not yet achieve a perfect reconstruction of the physical environment. On the right is an early reverse-passthrough prototype. On the left is an Oculus Rift that blocks the view of the VR user’s eyes. ![]() Meta Quest Pro is supposed to improve this display mode noticeably with a higher resolution and color. Meta Quest 2, for example, offers a passthrough mode in grainy black and white. This technology, called passthrough, already exists in commercially available VR headsets, if in rather poor quality. Headset sensors record the environment and display it as a video image in virtual reality. This both for reasons of user comfort and of social acceptance. VR users should be able to see the environment as much as the environment can see the VR users. The perfect VR headset must be translucent in both directions. The current prototype is so heavy that it hangs from the ceiling – and is extremely energy-hungry.Īccording to Meta, HDR contributes more to visual realism than, say, resolution and variable focus, but is the furthest from practical implementation. Starburst can realistically simulate lighting conditions in closed rooms and night environments. ![]() Mark Zuckerberg holds the Starburst prototype. ![]() Harbour the desire to live somewhere wacky? The incredible new apartment block in Amsterdam that's shaped like a ship - and looks like it's floating on waterĭitch the sunlounger - and go wild! From hearing the howl of wolves in Italy to watching eagles swoop in remote Scotland, the best breaks for incredible animal encounters Google Maps launches eco-friendly routing feature in UK: Tool highlights fuel-efficient roads with fewer hills and less traffic to help drivers save money on petrol and cut emissions ![]() and a ban on under-12sĬheers to the Czechs! A trip to Prague and nearby Pilsen offers Gothic grandeur, friendly locals - and plenty of good beerĪn enchanting Scottish woodland, a stunning 'UFO cloud' and mist spilling over mountains in Italy: The amazing winners of the 2022 iPhone Photography Awards Great British boltholes: Inside Merchants Manor in Falmouth - a classy getaway for grown-ups thanks to a bijou spa, an indoor pool. Glamping with giants: Pack your trunk to bed down with elephants in amazing bubble tents deep in the jungles of Thailand Italy's fab five: The string of colourful clifftop villages that make up Cinque Terre remains one of the world's most spectacular coastal landscapes - here's how to enjoy its highlights Guilt-free cruising: The amazing new cruise ships that are green, clean and luxurious, from ice-breaking expedition vessels to swanky river boats You'll be thunderstruck! From a monster storm cloud in Australia to a VERY long train in the Sahara - the incredible winners of the 2022 Drone Photo Awards revealedĪ talented flock of photographers! The spellbinding winners of the 2022 Bird Photographer of the Year awards revealed The Crete Late Show: Head to the south of the island where it's warm and welcoming well into October - and affordable too the ultimate Greek paradise: Inside the dreamy island where cars (and mopeds) are banned - and it's just 90 minutes from Athens by ferry ![]() Is THIS the most stunning place to stay in the French capital? Inside the uber-luxury Cheval Blanc Paris, which boasts Europe's largest indoor hotel pool and pinch-me views so which hotspot will YOU choose for a holiday that leaves you walking on water? ![]() Nothing beats the awesome views from the world's coolest infinity pools. Prices include scheduled flights to Chicago returning from Los Angeles, fourteen nights’ room-only accommodation, all state and local taxes, transfers and the services of a Travelsphere Tour Manager. Prices for the ‘Buddy Holly Experience’ start from £1,874 per person. There will also be excursions to Palo Duro Canyon State Park, Petrified Forest National Park and the Grand Canyon. There’ll also be the chance to see Lubbock’s tribute to the star - the impressive bronze Buddy Holly Statue - as well as Holly’s grave.Īmarillo is close to Route 66 so the 17-day tour will then take the music fans along the historic highway, stopping off at Los Angeles, Oklahoma, St Louis, Springfield and Chicago along the way. The tour takes in Holly’s first home, where the singer and his band The Crickets regularly rehearsed, Lubbock High School, where Buddy was a pupil, the house in which he married his young bride Maria Elena Santiago and the KDAV Radio Studios where Holly and the Crickets cut their first record. There'll be a chance to see Lubbock's impressive bronze Buddy Holly Statue See more ideas about funny text messages, funny texts, funny. Wake up and enjoy yet another pointless, indolent day that brings you nothing except the prospect of another one like it. short funny good morning texts to make him laugh with quotes. By finding Funny text messages to send your female friend, you can make the bond between you grow stronger as not all girls are attracted to money. Explore Max Miller's board 'Funny Text Messages', followed by 132,741 people on Pinterest. Whether you set an alarm or not, the dawn will come. Others go to the extents of buying them expensive prices. Have you found any funny educational quotes or photos? I’d love to see them share the link in the comments. Most boys tend to find it hard to make their female girlfriends smile. Good thing there’s mobile phones nowadays. She’s always using words that she doesn’t really know what they mean. We have a tream of specially trained monkeys who spend hours each day surfing the web for. Our goal is to provide you with a steady stream of funny pictures several times a week, year round. Haha this one makes me think of my Little Miss Nearly Three. Thanks for visiting the funny pictures section of - We have been bringing you the best funny pictures from all around the internet since 2006. Start now its free Drag your photo here to get started You can also open any image by simply dragging it into this window We could not open your image. This one’s for all you teacher librarians out there □ AddText is the quickest way to put text on photos. No one told me about this little chest nut when I became a teacher….who needs to go to the toilet anywhoo. Oh yeah does this sound like some of the kids in your class? When husbands text, things invariably go awry. Haha I love a bit of Simpson humour….yeah who needs English anyway….doh!!! 29 Dirty but Funny Texts Only Guys Would Send. Did you know this has been shared over 39 000 times on Facebook, sounds like a fair few teachers also find it funny. I first saw this one on Facebook and laughed out loud. Mmmm long gone are the days when an apple for the teacher would cut it, now it’s all about the coffee!Īhhh there’s nothing like a bit of punctuation humour, hehehe This one is for all my teaching buddies that are about to head on their summer break. ![]() iPhone text message quotes, Facebook funny status updates, geeky humor. I’ve put together some very funny educational pictures that I thought you might like too, enjoy! 1. Huge collection of funny photos of all kinds: cats, trolls, memes, funny quotes. I was feeling a bit blue when I sat down to do some blog writing, so I thought…what better way to cheer myself up…but to look at funny photos. I thought I’d share with you a bit of a light hearted post this week. True huh, I’ve heard some pearler stories from kids during news time. “If you promise not to believe everything your child says happens at school, I’ll promise not to believe everything he says happens at home.” ~ Anonymous ~ This mode has previously been available in the European Opel Ampera but this is the first time EV Hold Mode is offered in the Chevy Volt. In EV Hold Mode, the range extending engine will immediately provide regenerative charging to the battery so that when you finish the highway portion of your trip – you still have plenty of battery power to drive in stop-and-go traffic where EV mode is the most beneficial and efficient. ![]() This mode is ideal for drivers who leave home with a fully charged battery with the beginning portion of their drive taking place on the highway where electric power is depleted the most quickly. This will allow the driver to force the Voltec drivetrain to run with the gasoline engine running rather than relying on the battery power. ![]() In addition to the larger and more functional battery, the 2013 Chevrolet Volt will offer the EV Hold Mode. I would expect that with these increases in EPA ratings, private owners will find even better figures in terms of the all-electric range, overall range and fuel economy. Mind you, when driving the Volt to get an average over 8 days of 109mpg, I drove the car just as I would my personal vehicles which included highway drives with speeds over 70mph…showing that you don’t need to baby the Volt to get great fuel economy. Volt owners have repeatedly proven that the EPA mileage estimates are just that – estimates – and in the real world figures may be better with reasonable driving. ![]() I should point out that in my time spent behind the wheel of a 2012 Chevrolet Volt, I got between 38 and 43 miles on all-electric power while also averaging a very impressive 109 miles per gallon. “This attention to detail will allow our customers to experience more pure EV range, which is the true benefit of owning a Volt.” We’ve done some work at the cell level to modify the ‘ingredients’ to make a better end result,” said Bill Wallace, GM director of Global Battery Systems Engineering. Sometimes if you use more sugar and less vanilla you get a better tasting cake. “The best way to explain what we’ve done at the cell level is to compare it to a cake batter recipe. The only downside to the 2013 Chevrolet Volt is that here is a slight increase in charge time of a half hour when charging via a 120V port and 15 minutes when connected to a 240V line. Finally, the overall EPA range when starting when a charged battery and full tank of gas is 380 miles, a small increase of 1 miles over the previous year but a small increase is better than no increase. Next, the MPGe (mile per gallon equivalent) has increased from the figure of 94 miles per gallon for the 2012 model year to 98 MPGe for the 2013 Volt. The 2012 Chevy Volt offered an EPA electric range of 35 miles so for 2012, there is an increase of 3 miles range for the new model year. Well, the 2013 Chevrolet Volt offers 38 miles of all-electric range, according to the official EPA ratings that will appear on the window sticker. These figures are all well and good but what do these increases equate to in real world figures? This 10.8 kWh window is there to prevent the battery from being drained too far as, when a battery is drained empty over and over – it decreases the life of the battery. What does this all mean? It means that the battery of the 2013 Chevy Volt can hold more juice and the Voltec drivetrain can use more of that available energy before the range-extending gasoline engine kicks in. First of all, the 2013 Chevrolet Volt features an increased battery power capacity, up to 16.5 kWh from 16.0 kWH in the 2012 Volt while the available usage of battery energy has expanded from 10.3 kWh to 10.8 kWh. ![]() Which is a shame, considering what a powerful tool they can be. Assuming that it wasn’t created for them, some don’t explore the cards at all. Understandably, when a person cannot even see themselves authentically reflected in the cards, it can leave them feeling missing from the equation. To help you find out, PBS NewsHour partnered with the Pew Research Center to create a simple quiz that helps calculate your partisan status and how you compare with others based on your age. Oracle card decks can be given pretty much any theme you can think of-be it unicorns or angels or pop music icons-and yet, very few feature diverse images or delve into minority cultures. With all the biases out there in the world today, it can be challenging to know which political party your ideals line up with the most. But do you really Take this quiz to find out. Plus they’re endlessly fun and who doesn’t love pretty things? You may think you know what someone from another political party believes. Sure, they’re a common staple of a modern-day spiritual practice, but the main reason I adore them, and why these little cards have become so mainstream over the years, is that they can be valuable self-reflection tools, helping us to make new connections, break old patterns and creatively work on personal development. Each card has a symbolic picture along with a simple, yet poignant message, usually of the empowering variety. You’ve probably heard of tarot cards-oracle cards are like tarot’s laid-back younger sibling. My favorite thing to do is gift someone their first oracle card deck. Whether it be from a crystal, intention-setting candle or meditative bath bomb, I love seeing the look of fascination and intrigue on a loved one’s face after receiving a bit of magic. Most democrats believe the few jobs that would be created by going green would combat the. ![]() Democrats tend to take a more liberal stand on issues such as abortion, same-sex marriage, and immigration. In all my friend groups, I am considered a bit of a woo ambassador. Democrats are sometimes referred to as the Party of the People, attracting immigrants, LGBTQ, women, and minorities. Take This Quiz & Well Tell You Which Political Party Youre Secretly Part Of. Addition of subtitles into any video for easy understanding.Advanced translation of these devices into 30 different languages.Automatic transcription of files and accessibility of these files from any device.This application offers a 30-minute free transcription after which an affordable amount may be charged. Sonix is a fast and accurate application that can be used to convert audio to text for any purpose. Transcription costs for one hour are $12.Offers an option of easy upload and export of files.Supports a variety of audio and video formats like MP3, WAV, MP4, etc.An inbuilt editor for editing the text while transcribing.The transcription to text is done with the use of an advanced AI and hence produces faster and more accurate results.Īudext is used by people from different sectors like education, marketing, media, consulting, healthcare, etc. Yearly plan: 4-hour transcription - $2.99/monthĪudext is a free online application that can help you to save a lot of time while transcribing any audio to text.Monthly plan: 4-hour transcription - $9.99/month.You can edit the converted audio to text via typing, splitting, deleting unwanted text, copying and pasting, and adjusting the playback duration to create a perfect sync between the text and the audio or video. The editing features available on this tool are vast, making for a better output file.It supports over 100 world languages ranging from the English language, Spanish, French, Swedish, Estonian, Russian, etc.It supports multiple file formats such as MOV, MP3, MP4, OGG, MTS, FLAC, etc.It quickly detects the speech in an audio message and uses AI tech to convert it to text.It uses an AI text generator that automatically converts any uploaded audio or video to text in a short time. Moreso, this audio-to-text converter is helpful to podcasters who can upload the text to enable listeners to follow the inspirational message being passed across. When you convert a sound to text on this tool, you can use it as a subtitle or caption for your video. It is fast, easy, and accurate in its transcription. ![]() Media.io is a free online tool that auto transcribes any audio file you upload on it into a text. Here we will talk about the top 11 free applications that can be used to convert audio to text 1. Some of these recorders can convert any audio file to texts while some others can record and convert to text at the same time. There is number of audio text converters available in the online market that can help you while studying, researching, or even in your business. So let’s have a look at some of the best audio-to-text converters that might be of use to you. And texts can also easily be shared with whomever you want. Information in the form of text can easily be fully or partly accessed and edited whenever needed. ![]() From online classes and long lectures to big business meetings and product information, audio is being shared a lot across the world.īut accessing information from a long audio file can be difficult and time-consuming, which is why there is a need to convert audio to text. Audio files are one of the most used methods of storing information. ![]() An audio-to-text converter is a tool that can convert audio files to texts or even record any audio and produce the text of it simultaneously. ![]() Who knows, maybe playing something like Grabble or Word Detector will help you get a little bit better of a grade in your next spelling test without even feeling like you were studying. Getting to learn while having fun can often be difficult, but word games are a great way to learn in an exciting way. Maybe best of all, word games will improve your spelling without it feeling like school. A few other games like this include Candy Word and Word Worm, both of which make spelling a whole lot more fun than you would think possible. By spelling words correctly, you will be rewarded with abilities like extra platforms and more jumps. As mentioned before, the game Misspelled is a game where you use magic to get through the levels. From popular spelling games like SCRABBLE and Word Whomp to classic crosswords and word searches, we’ve got you covered. Word games are one of the best ways to improve brain function and bolster key language skills. Several titles are more like regular games that happen to have words as a part of them. Give yourself a mental workout with free online word games on Pogo. We have developed a special edition for kids with a dictionary for children up to 8th grade, and the ability to select a target word from 3 letters to 11 letters.There are plenty of riffs on word games on our Word Games Playlist! Pretty much all of our playlists on Coolmath Games have fun spins on the ordinary genre, and the Word Games Playlist is no exception. This game will be especially useful for children to develop memory and logical thinking skills. Then any revealed hints must be used in subsequent guesses. You can make the game harder by turning on "Hard Mode" in the settings. Now you can play in American English, UK English, Spanish, French, German, Portuguese, Italian, Dutch, Russian, Polish, Swedish, Irish, Czech, Greek, Turkish, Indonesian, and Filipino. We have developed many versions of the Wordle Game for different languages and dictionaries. If this word is found in our word bank, the link will be copied to the clipboard and then you can easily share it on social media. Can I guess a word to challenge my friends?Ĭertainly! Just click on the icon (W+) in the top left corner, then guess any word from 4 to 11 letters (without spaces, hyphens, apostrophes) and click the "Copy Link" button.Everybody knows how important typing is and so has a variety of typing games so that you can practice and see the words fly on the screen. Play games like hangman, word search, texttwist 2, word wipe, word connect or test your vocabulary. Our free online word games can be played from a desktop computer, a tablet or a mobile phone, and they are instantly available, with no installation required. But you can bookmark the site and play on PC or mobile devices right in your browser. Play the best free Online Word Games and Letter Games. If you want to change an incorrectly entered letter, just press the "Backspace" button, but remember that you cannot change the entered word.Īt the moment we don’t have applications in App store and Google Play (in development). We will definitely fix this as soon as possible. If you think that the hidden word is wrong or incorrect, let us know. Play Wordle with unlimited words Guess words from 4 to 11 letters in different languages and create your own puzzles. Try another word, or if you think the word is correct, let us know. This alert message means that the given word was not found in our word bank. Why did I get a "Word not found" message?.Anagrams Bookworm HD Game Tile Bookworm HD. This dictionary is constantly updated with new words based on real feedback from people. Play Free Online Word Games For All Ages A Way With Words Game Tile. In American English, we use a dictionary from the Letterpress word list that includes a list of ~275,000 words. However, mathematician Grant Sanderson found that the best starting word is “CRANE" or “SLOTH”, which includes frequently used letters. What is the best word to start the game?Īt the beginning of the game, try to use a word without repeating letters and with as many vowels as possible, such as the word "RADIO".To win you need to completely guess the hidden word (all letters are green). The letter is in the word and in the correct spot. The letter is in the word but in the wrong spot. The letter isn't in the target word at all. Depending on which word you entered, the letters will be highlighted in three colors. In each line, you need to enter any word from 4 to 11 letters to find out what letters are in the target word. The main goal of the game is to guess the hidden word in 6 tries. The report covers analysis and forecast of 18 countries globally along with current trend and opportunities prevailing in the region. The air deflector market by each region is later sub-segmented by respective countries and segments. It also provides market size and forecast estimates from year 2020 to 2028 with respect to five major regions, namely North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South America. It provides overview and forecast of the global air deflector market based on various segments. The report provides a detailed overview of the industry including both qualitative and quantitative information. ![]() On the basis of vehicle type, the market is segmented as passenger cars and commercial vehicles. On the basis of type, the market is segmented as window deflectors, sunroof deflectors, and bug deflectors. On the basis of material, the market is segmented as acrylic, ABS plastic, and others. The global air deflector market is segmented on the basis of material, type and vehicle type. The report provides key statistics on the market status of the leading air deflector market players and offers key trends and opportunities in the air deflector market. The global air deflector market is expected to witness high growth during the forecast period. The report aims to provide an overview of air deflector market with detailed market segmentation by material, type, vehicle type and geography. The "Global Air Deflector Market Analysis to 2028" is a specialized and in-depth study of the air deflector market with a special focus on the global market trend analysis. Furthermore, the growth in passenger cars and commercial vehicles is likely to drive the air deflector market during the forecast period. However, the high initial cost may restrain the growth of the air deflector market. The growth in sales of SUVs that need effective aerodynamics drives the global air deflector market. The growing sales and production of vehicles and high spending by consumers on vehicle service and up-gradation are estimated to surge the demand for the air deflector market during the forecast period. It prevents rushing air from entering the vehicle and gives a better look to the vehicles. During low speeds, it is retracted and enables air to flow beneath the vehicle. It guides the air flow and optimizes the aerodynamics of the vehicle. The air deflector helps to direct the air flow from a vent hooked to the ventilation system and connects various ways. Minimally Invasive/Non-Invasive Surgery.Aerospace & Defense Systems & Technologies. ![]() We previously used CGS-21680, an adenosine agonist 13, to simulate elevated adenosine A 2A inhibitory signalling in response to high levels of adenosine in the hypoxic TME 15. ![]() We developed a systematic approach to identify genetic perturbations that could render T cells resistant to a range of inhibitory signals encountered in the TME. The suppressive TME and T cell intrinsic checkpoints can impinge on the efficacy of engineered T cells targeting solid tumours 14. Finally, we show that RASA2-ablation in antigen-specific T cells can enhance tumour control and extend survival in multiple preclinical models of liquid and solid tumours. We find that ablation of RASA2 enhances sensitivity to antigen and improves both effector function and persistence of CAR T and TCR T cells. Here we describe unbiased genetic screens performed under several immunosuppressive conditions commonly encountered in the tumour microenvironment (TME) that uncovered ablation of the RASA2 gene as a strategy for T cells to overcome multiple inhibitory cues. We previously developed a discovery platform in primary human T cells and applied it to identify novel genetic regulators of T cell proliferation 13. Large-scale CRISPR screens can accelerate the discovery of genetic perturbations that can boost the efficacy of engineered T cells 3, 8, 9, 10. However, the optimal gene targets in human T cells have not been explored systematically. Targeted manipulation of select genes is being tested as a strategy to boost the efficacy of adoptive T cell therapies 5, 6, 7. In addition, persistent exposure to antigen can lead to T cell dysfunction, highlighting the need to balance effector function and long-term persistence in engineered T cells 3, 12. Within the tumour mass, the immunosuppressive microenvironment poses a substantial barrier to the efficacy of anti-tumour immunity 2, 11. However, many cancers, especially solid tumours, do not respond to current T cell therapies or rapidly progress after the initial response. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.ĬAR T cells have been transformative in a subset of aggressive haematological malignancies, and T cell receptor (TCR)-transgenic T cells (TCR T cells) have shown promising results in early-phase clinical studies for solid tumours 1. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. ![]() Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function 3, 4, 5, 6, 7, 8, 9, 10. The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints 1, 2. Nature volume 609, pages 174–182 ( 2022) Cite this article RASA2 ablation in T cells boosts antigen sensitivity and long-term function |
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