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Myelomonocytic cells are part of tumour-extrinsic pathways of primary and adaptive resistance to ICB88 by expressing several immunosuppressive molecules, including checkpoint ligands, such as PDL1, PDL2, CD80 (also known as B7-1) and CD86 (also known as B7-2), and poliovirus receptor (PVR; also known as CD155 and one of the TIGIT ligands)12,51,89,90 (Fig. 1). PDL1 assessment by immunohistochemistry is approved as a companion diagnostic for anti-PD1 therapy in NSCLC and other tumours91,92, but its predictive capability may vary according to the cell type considered, such as tumour or immune cells93. In preclinical models, PDL1 expression on tumour-infiltrating immune cells but not on tumour cells was associated with response to anti-PD1 or anti-PDL192 antibodies. Unexpectedly, macrophages were reported to express PD1, which negatively correlates with their phagocytic activity against tumour cells94,95,96. Interestingly, myelomonocytic cells express other counter-receptors that interact with negative regulators expressed by T cells and natural killer (NK) cells. VISTA is expressed by macrophages97 and interacts with P-selectin glycoprotein ligand 1 (PSGL1)98, functioning as a T cell checkpoint inhibitory ligand. In human monocytes, mAbs against VISTA elicited transcriptional and functional changes, including increased antigen presentation, activation and migration99.
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With the idea to combine the precision of a therapeutic antibody with the stimulation of innate immunity cells into a single agent, Ackerman et al. recently reported the design of BDC-1001, an immune-stimulating antibody conjugate, engaging TLR7 and TLR8 and conjugated to a tumour-targeting antibody against HER2. In mice, systemic administration of this immune-stimulating antibody conjugate successfully reduced tumour growth and stimulated an antitumour immune response mediated by macrophages and other antigen-presenting cells, without eliciting inflammation162. SBT6050 is a TLR8 agonist conjugated to a HER2-directed antibody. Both BDC-1001 and SBT6050 are under evaluation in a first-in-human trial in patients with HER2-positive tumours (Table 1).
Stimulator of interferon genes (STING) protein receives input from different cytoplasmic receptors that sense ectopic nucleotides from pathogens as well as from endogenous damaged DNA, leading to the production of type I interferon. Therefore, STING also has a key role in antitumour immune responses171,172. This property of STING generated attention and prompted the development of synthetic STING agonists173 (Fig. 2). In early times before the identification of STING, DMXAA (5,6-dimethylxanthenone-4-acetic acid), a vascular disrupting agent based on flavone acetic acid, was known to have anticancer activity mediated by interferon and TNF in experimental tumour models174. DMXAA is the best-known STING activator, and stimulation of STING in innate immunity cells (but also in cancer cells) successfully elicited antitumour immunity in several preclinical tumour models and synergized with radio-chemotherapy and immunotherapy172,173. Although compounds targeting the STING pathway are not macrophage specific, preclinical studies have demonstrated that activation of antitumour immunity engages infiltrating macrophages and dendritic cells. Because early pharmacokinetic studies showed that most STING agonists have a short half-life, novel compounds with improved half-life have been developed and are moving ahead for evaluation in patients with cancer173,175,176. Most frequently, STING agonists have been administered intratumourally; however, an available formulation for oral administration has been tested in mice and resulted in significant tumour regression and synergism with checkpoint blockade immunotherapy177. STING is also activated by microbiota-derived agonists, such as c-di-AMP, which regulate interferon production and macrophage polarization178. Interestingly, modulation of the microbiota with a high-fibre diet improved the efficacy of ICB178.
A network of transcription factors, epigenetic modifications and mRNAs underlies the plasticity and polarized activation of macrophages4,5,7. Downstream rewiring of macrophage function involves profound changes in amino acid, lipid and iron metabolism219,220,221. This complex cascade provides potential targets to reprogramme macrophage function. Epigenetic regulation by inhibition of class IIa histone deacetylases (HDACs) is a promising approach to harness the antitumour potential of macrophages. TMP195 was identified as a selective class IIa HDAC inhibitor that was able to modify the transcription profile of macrophages. In preclinical breast cancer models, TMP195 resulted in a macrophage-mediated reduction of tumour growth222. Tefinostat (CHR-2845) is an HDAC inhibitor that is cleaved to an active acid by non-specific esterase liver carboxylesterase 1 (CES1), the expression of which is limited to cells of monocytoid lineage and some hepatocytes, allowing selective accumulation of active drug within monocytoid cells. Because of this feature, it has been successfully used in a phase I clinical trial in patients with advanced haematological malignancies such as myelodysplastic syndromes and chronic myeloid leukaemia (NCT00820508)223. In principle, CES1 may provide a tool to develop macrophage-selective targeting of drugs.
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Nov. 18, 2000Box ScoreLOS ANGELES - USC showed it can score in itsseason-opener. Now, coach Henry Bibby wants to see some defense.Sam Clancy scored a career-high 31 points and all five USC starters reacheddouble figures as the 23rd-ranked Trojans beat Bradley 107-92 Saturday night."We didn't play with the intensity I'd like. Maybe it was first-gamejitters," Bibby said. "I'd like to see more of a killer instinct."Clancy, a junior who missed 10 games last season because of a broken foot,sent the Braves to their 10th straight defeat against a Top 25 team in thefirst meeting between the schools since 1974.Jerome Robinson, the last player cut from Canada's Olympic basketball team,led the Braves with a career-high 31 points. Freshman Phillip Gilbert, a formerhigh school teammate of Los Angeles Clipper rookie Darius Miles, added 22points.Trailing by one at halftime, the Trojans outscored Bradley 20-9 to start thesecond half. A putback by Clancy gave the Trojans their first double-digit leadof the game, 68-58, with 15:40 remaining.The Braves had three starters in foul trouble at the break. Reggie Hallpicked up his fourth foul seconds into the second half and Jeffrey Rabey addedthree fouls in the first two minutes to give him four.USC made 18 of 24 free throws in the second half when the Braves were forcedto foul."I thought a key to the game was we put them into the bonus with 17 minutesto go in the game," Bradley coach Jim Molinari said. "That took away some ofour aggressiveness."Bradley shot 75 percent in the first half and led by six three times. TheBraves finished the game shooting 60 percent from the field, 65 percent fromthe line and 61 percent from 3-point range."I haven't seen a team shoot the way Bradley did," Bibby said. "We shouldhave fouled them more."USC's David Bluthenthal, who missed both preseason games while recoveringfrom arthroscopic knee surgery, had 23 points and 13 rebounds. He made all fourof his free-throw attempts, extending his streak of consecutive foul shots to37, dating to the final seven games of last season, and tying the school recordset by John Block.The Trojans scored 100 points for the first time since beating San DiegoState 101-54 to open the 1999 season. The Braves hadn't had an opponent go overthe century mark since they beat Loyola of Chicago 111-107 on Dec. 23, 1988, aspan of 309 games."This was a measuring stick for us on how far we have to go," Bibby said."We can be as good as we want to be. That will be determined by the players."The Trojans played without Jeff Trepagnier, who is expected to start atguard for his third straight season. He missed both preseason games whilerecovering from a hairline fracture in his left foot."We'll sit Trepagnier as long as we can to get him healthy," Bibby said."Maybe it'll be one, two, three, four games. He can run and cut, but he stillfeels a bit of pain."The Braves were without sophomore guard Andre Corbitt and junior forwardJermaine Brown. Corbitt was suspended for the opener as a result of analtercation at a party last weekend. He traveled with the team, but didn'tdress. Brown left the team this week.By BETH HARRISAP Sports Writer
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Only","type":"single","effect":"none","fixed_image_sizes":false,"excluded_sport_ids":[],"slick":false,"dfp":false,"sidearm_dfp":false,"common_page":false,"html_template":null,"name":"polite-pop-up---schedule-only-62ac9b","autoplay_speed":8,"accessibility_icons":true,"sizes":null,"slick_options":null,"dfp_sizes":null,"campaigns":[],"content_id":"polite-pop-up---schedule-only-62ac9b","content_title":"polite-pop-up---schedule-only-62ac9b","content_date":null,"content_url":null,"content_image_url":null,"mode":"web"; if (!("sidearmComponents" in window)) window.sidearmComponents = []; window.sidearmComponents.push(obj); function setPoliteScheduleCookie(id) let date = new Date(); date.setDate(date.getDate() + 30); document.cookie = 'sa-polite-popup--schedule-' + id + '=true; expires=' + date.toUTCString() function newScheduleVisit(id) if (document.cookie.split(';').filter((item) => item.trim().startsWith('sa-polite-popup--schedule-' + id + '=')).length) return false; else return true; function initSchedulePopup() let _id = ko.contextFor($('.c-polite-pop-up--schedule__content .single-ad')[0]).$data.id; let popup = document.getElementById('polite-pop-up--schedule'); let close = document.getElementById('polite-close--schedule'); if (newScheduleVisit(_id) && window.matchMedia('(min-width:1px)').matches) //sets cookie automatically on load //setPoliteScheduleCookie(_id); close.addEventListener('click', (e) => e.preventDefault(); popup.classList.remove('is-active--schedule'); //sets cookie on close click setPoliteScheduleCookie(_id); ); setTimeout(() => popup.classList.add('is-active--schedule'); , 3000); else console.log('in init else'); popup.parentNode.removeChild(popup); return; require(['knockout', 'jquery'], function (ko, $) let attemptsToRun = 0; let popupSetter = setInterval(function () if ($('.c-polite-pop-up--schedule__content .single-ad').length) initSchedulePopup(); clearInterval(popupSetter); if (attemptsToRun > 20) //not always going to exist so let's kill it after a while clearInterval(popupSetter); ++attemptsToRun; , 500); ); var obj = "start":0,"count":10,"name":"polite-pop-up-f1074e","sport_id":null,"count_breakpoints":null,"css_class":"","pinned_id":"","extra":,"context":null,"dummy":false,"type":"ads","id":"6d9ce70e-f036-439b-95e7-e72e30880c64","data":"location":"id":1166,"title":"Polite Pop-Up","type":"html","effect":"none","fixed_image_sizes":false,"excluded_sport_ids":[],"slick":false,"dfp":false,"sidearm_dfp":false,"common_page":false,"html_template":null,"name":"polite-pop-up-f1074e","autoplay_speed":8,"accessibility_icons":true,"sizes":null,"slick_options":null,"dfp_sizes":null,"campaigns":["id":2409,"title":"Polite Pop-Up Ad","start_date":"2022-03-30T16:34:00","end_date":null,"open_in_new_window":true,"link":"#","icon":null,"html":"\r\n\r\nSign up for VictoryMail to receive exclusive discounts, ticket offers, and news delivered to your inbox.\r\n\r\n\r\n","picture":null,"css_class":null,"is_dummy":false,"hover_text":null],"content_id":"polite-pop-up-f1074e","content_title":"polite-pop-up-f1074e","content_date":null,"content_url":null,"content_image_url":null,"mode":"web"; if (!("sidearmComponents" in window)) window.sidearmComponents = []; window.sidearmComponents.push(obj); function setPoliteCookie(id) let date = new Date(); date.setDate(date.getDate() + 30); document.cookie = 'sa-polite-popup-' + id + '=true; expires=' + date.toUTCString() function newVisit(id) if (document.cookie.split(';').filter((item) => item.trim().startsWith('sa-polite-popup-' + id + '=')).length) return false; else return true; function initPopup() let _id = ko.contextFor($('.c-polite-pop-up__container .html-ad')[0]).$data.id; let popup = document.getElementById('polite-pop-up'); let close = document.getElementById('polite-close'); if (newVisit(_id)) //sets cookie automatically on load // setPoliteCookie(_id); close.addEventListener('click', (e) => e.preventDefault(); popup.classList.remove('is-active'); //sets cookie on close click setPoliteCookie(_id); ); setTimeout(() => popup.classList.add('is-active'); , 3000); else popup.parentNode.removeChild(popup); return; require(['knockout', 'jquery'], function (ko, $) let attemptsToRun = 0; let popupSetter = setInterval(function () if ($('.c-polite-pop-up__container .html-ad').length) initPopup(); clearInterval(popupSetter); if (attemptsToRun > 20) //not always going to exist so let's kill it after a while clearInterval(popupSetter); ++attemptsToRun; , 500); ); require(['jquery', 'headroom', 'jquery-headroom'], function($) var $html = $('html'); var offset = 48; $(function() $(window).resize(function() if ($html.hasClass('ticker-visible')) offset = 96; else if (window.matchMedia('(min-width:1025px)').matches) offset = 36; else offset = 48; $html.headroom('destroy').removeData('headroom').headroom( offset: offset ); $('#polite-pop-up').headroom('destroy').removeData('headroom').headroom(offset: 300); ).trigger('resize'); ); window.showTicker = function() $html.addClass('ticker-visible'); $html.headroom('destroy').removeData('headroom').headroom( offset: 96 ); setTimeout(function() $('.content-ad--sticky').addClass('can-close'); , 5000); ); require(['jquery'], function($) // Hide Faceoffs Won for WLAX setTimeout(function() if ($('.roster-page.wlax .sidearm-visual-text-stat-title').length) $('.roster-page.wlax .sidearm-visual-text-stat-title:contains("Faceoffs Won")').parent().remove(); , 100); ); //For rosters and schedules, condense Men's and Women's to M and W in title on mobile //wait for element to exist then run code, stop if counter exceeds limit var limitCounter = 0; var checkExist = setInterval(function() limitCounter === 10) document.documentElement.clientWidth else limitCounter++; , 500); // check every 500ms window.accessibility_focus_outline_style = 'solid'; window.accessibility_focus_outline_color = '#ffc72c'; window.accessibility_focus_outline_width = '5px'; window.accessibility_light_mode = 'true'.toLowerCase(); Opens in new window Opens in new window Opens in new window Opens in new window Opens in new window Opens in new window Search Go Search: window.preloaded_templates_are_rendering = true; require(['knockout'], function (ko) function register_custom_loader(component, vm_name, template_name) register_custom_loader('ads', 'promotions', 'promotions'); register_custom_loader('dfp', 'evergreen', 'evergreen'); register_custom_loader('navigation');register_custom_loader('search'); window.preloaded_templates_are_rendering = false; ); Ad Blocker Detected Thanks for visiting ! 2ff7e9595c
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