{"entity":{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","aka":[],"tldr":"Most tumours keep the immune system out or asleep, so immunotherapy helps only a minority.","summary":"Checkpoint blockade is the one therapeutic advance of the last two decades for which more than two fifths of US cancer patients are eligible, yet it works durably in a minority of patients and barely at all in several of the cancers that kill the most people. Pancreatic, prostate, most breast and microsatellite-stable colorectal cancers and glioblastoma are 'cold': few infiltrating T cells, low neoantigen load, dense desmoplastic stroma, abundant myeloid suppressor cells and regulatory T cells, hypoxia, and metabolic competition that starves effector cells. Even in 'hot' tumours, exhaustion and antigen loss limit durability. The field has many candidate mechanisms and many single-agent attempts (IDO, TIGIT, STING agonists, oncolytic viruses, CD47) that have failed in phase 3 because the biology of each tumour's exclusion is different and largely unmeasured. Converting cold tumours, or bypassing the microenvironment with engineered cells, bispecifics and radioligands, is the central strategic problem in immuno-oncology.","asOf":"2026-09-08","links":[{"label":"Haslam & Prasad, Estimation of the percentage of US patients eligible for and responding to checkpoint inhibitors (JAMA Netw Open 2019)","url":"https://doi.org/10.1001/jamanetworkopen.2019.2535"},{"label":"Chen & Mellman, Elements of cancer immunity and the cancer-immunity set point (Nature 2017)","url":"https://doi.org/10.1038/nature21349"},{"label":"Binnewies et al., Understanding the tumor immune microenvironment (Nature Medicine 2018)","url":"https://doi.org/10.1038/s41591-018-0014-x"}],"tags":[],"related":["idea-immunotherapy-mss-crc","idea-fap-theranostics-pancancer","idea-mesothelin-car-t-regional","idea-photoimmunotherapy-plus-pd1","immunotherapy-roadmap","cellxgene-hca","idea-bio2-trem2-myeloid-reprogramming","idea-bio2-in-situ-vaccination-solid","idea-bio2-oncolytic-regulated-il12","idea-bio2-engineered-bacteria-payloads","idea-bio2-tumour-anchored-tgfbeta-trap","idea-bio2-lactate-acid-axis","idea-bio2-radiotherapy-sting-fractionation","idea-bio2-tertiary-lymphoid-induction","idea-bio2-cxcr2-neutrophil-blockade","idea-bio2-caf-subtype-assignment","idea-bio2-implantable-microdevice-screen","idea-bio2-vascular-normalisation-window","idea-bio2-complement-c5ar-blockade","idea-bio2-intracavitary-immunotherapy","idea-bio2-myeloid-engager-bispecific","idea-bio2-hypoxia-guided-adenosine","idea-bio2-histotripsy-immune-priming","idea-bio2-trained-immunity-priming","idea-moon-cold-to-hot-programme"],"cancers":["pancreatic","prostate","colorectal","glioblastoma","breast-hr-positive","ovarian"],"sections":[],"technologies":["checkpoint-inhibitor","t-cell-engager","sting-agonist","oncolytic-virus","neoantigen-mrna-vaccine","car-t","photoimmunotherapy","single-cell-spatial","cytokine-therapy"],"targets":["pd1","pdl1","ctla4","lag3","tigit","fap","cd47","dll3"],"drugs":["tarlatamab","fap-2286","intismeran-autogene","autogene-cevumeran","vusolimogene-oderparepvec","tiragolumab","magrolimab","epacadostat","adu-s100"],"companies":["moderna","biontech","replimune","10x-genomics"],"institutions":[],"pathways":["pd1-checkpoint","cgas-sting"],"terms":["cold-vs-hot","tils","tmb","msi","desmoplasia","neoantigen","immunogenic-cell-death","abscopal-effect"],"trials":["keynote-177","checkmate-8hw","niche-2","napoli-3","interpath-001"],"people":[],"bottlenecks":[],"keyPapers":["paper-haslam-jama-netw-open","paper-chen-nature"],"journals":[],"dependsOn":[],"notes":[],"stage":"biology","severity":"critical","metrics":[{"label":"US patients with cancer eligible for a checkpoint inhibitor (2018)","value":"43.6%","source":"Haslam & Prasad, JAMA Network Open 2019","url":"https://doi.org/10.1001/jamanetworkopen.2019.2535"},{"label":"US patients with cancer estimated to respond to a checkpoint inhibitor (2018)","value":"12.5%","source":"Haslam & Prasad, JAMA Network Open 2019","url":"https://doi.org/10.1001/jamanetworkopen.2019.2535"},{"label":"Median progression-free survival with pembrolizumab vs chemotherapy in MSI-high colorectal cancer (KEYNOTE-177), showing the gain when a cold cancer is immunogenic","value":"16.5 vs 8.2 months","source":"André et al., NEJM 2020","url":"https://doi.org/10.1056/NEJMoa2017699"}],"causes":["Low mutational burden yields few neoantigens for T cells to recognise.","Desmoplastic stroma and abnormal vasculature physically exclude lymphocytes.","Myeloid-derived suppressor cells, tumour-associated macrophages and regulatory T cells actively switch off effector cells.","Hypoxia, lactate, adenosine and nutrient depletion in the tumour disable T-cell metabolism.","Loss of MHC class I and antigen-presentation machinery makes tumours invisible even when T cells are present.","Combination trials have mostly added agents empirically without a biomarker for the specific exclusion mechanism."],"currentEfforts":["T-cell engagers and CAR-T bypass the need for endogenous priming; tarlatamab (DLL3) and mesothelin or GD2 CAR-T show that engineered T cells can act in solid tumours.","STING agonists, oncolytic viruses (RP1, T-VEC) and photoimmunotherapy are being tested as in situ vaccines to turn cold lesions hot.","FAP-targeted radioligands and FAP theranostics attack the fibroblast stroma directly.","Neoantigen mRNA vaccines (Moderna/Merck intismeran, BioNTech autogene cevumeran) aim to generate T-cell responses where none exist, including in pancreatic cancer.","Trials in MSS colorectal cancer combine checkpoint blockade with VEGF, MEK or bispecific agents, and NICHE-2 showed dramatic neoadjuvant responses in dMMR disease.","Spatial transcriptomics and multiplex imaging (10x Genomics, Human Cell Atlas) are being used to classify exclusion mechanisms per tumour."],"successLooksLike":"A biomarker-defined strategy produces durable responses in a majority of patients with pancreatic, prostate, MSS colorectal or glioblastoma, and the fraction of all cancer patients who respond to immunotherapy rises from roughly one in eight to a majority."},"route":"/bottlenecks/b-tme-immunosuppression/","neighbours":{"idea":[{"id":"idea-bio2-tumour-anchored-tgfbeta-trap","kind":"idea","name":"Anchor a TGF-beta trap in the tumour stroma so it cannot act everywhere","route":"/ideas/idea-bio2-tumour-anchored-tgfbeta-trap/"},{"id":"idea-bio2-myeloid-engager-bispecific","kind":"idea","name":"Bispecific antibodies that engage macrophages instead of T cells","route":"/ideas/idea-bio2-myeloid-engager-bispecific/"},{"id":"idea-bio2-complement-c5ar-blockade","kind":"idea","name":"Block the complement signal that recruits tumour-protecting cells","route":"/ideas/idea-bio2-complement-c5ar-blockade/"},{"id":"idea-bio1-stromal-resistance-blockade","kind":"idea","name":"Block the survival signals the tumour's neighbours provide","route":"/ideas/idea-bio1-stromal-resistance-blockade/"},{"id":"idea-bio2-cxcr2-neutrophil-blockade","kind":"idea","name":"Clear the suppressive neutrophils out of pancreatic tumours first","route":"/ideas/idea-bio2-cxcr2-neutrophil-blockade/"},{"id":"idea-bio2-lactate-acid-axis","kind":"idea","name":"De-acidify the tumour so T cells can work in it","route":"/ideas/idea-bio2-lactate-acid-axis/"},{"id":"idea-bio1-lytac-surface-degraders","kind":"idea","name":"Drag cancer's surface and secreted proteins to the cell's recycling bin","route":"/ideas/idea-bio1-lytac-surface-degraders/"},{"id":"idea-bio2-engineered-bacteria-payloads","kind":"idea","name":"Engineered bacteria that live in tumours and manufacture drugs there","route":"/ideas/idea-bio2-engineered-bacteria-payloads/"},{"id":"idea-moon-engineered-immune-surveillance","kind":"idea","name":"Engineered immune surveillance: long-lived programmed immune cells that patrol for early cancer","route":"/ideas/idea-moon-engineered-immune-surveillance/"},{"id":"idea-fap-theranostics-pancancer","kind":"idea","name":"FAP theranostics as a pan-cancer stromal strategy","route":"/ideas/idea-fap-theranostics-pancancer/"},{"id":"idea-bio2-tertiary-lymphoid-induction","kind":"idea","name":"Grow immune command posts inside tumours","route":"/ideas/idea-bio2-tertiary-lymphoid-induction/"},{"id":"idea-bio2-implantable-microdevice-screen","kind":"idea","name":"Implant a tiny device that tests twenty drugs inside the patient's own tumour","route":"/ideas/idea-bio2-implantable-microdevice-screen/"},{"id":"idea-bio2-inhaled-lung-niche-immunotherapy","kind":"idea","name":"Inhaled immune therapy to make the lung hostile to arriving tumour cells","route":"/ideas/idea-bio2-inhaled-lung-niche-immunotherapy/"},{"id":"idea-reg-losartan-pancreatic-stroma","kind":"idea","name":"Losartan to loosen the stroma of pancreatic cancer before chemotherapy: a phase 3","route":"/ideas/idea-reg-losartan-pancreatic-stroma/"},{"id":"idea-moon-cold-to-hot-programme","kind":"idea","name":"Make every cold tumour hot: a coordinated programme to reprogramme immune-excluded tumours","route":"/ideas/idea-moon-cold-to-hot-programme/"},{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/"},{"id":"idea-bio2-caf-subtype-assignment","kind":"idea","name":"Match therapy to the type of scar-forming cell in the tumour","route":"/ideas/idea-bio2-caf-subtype-assignment/"},{"id":"idea-bio2-histotripsy-immune-priming","kind":"idea","name":"Mechanically pulverise one tumour with ultrasound to wake the immune system","route":"/ideas/idea-bio2-histotripsy-immune-priming/"},{"id":"idea-bio2-oncolytic-regulated-il12","kind":"idea","name":"Oncolytic viruses that make interleukin-12 only inside the tumour","route":"/ideas/idea-bio2-oncolytic-regulated-il12/"},{"id":"idea-photoimmunotherapy-plus-pd1","kind":"idea","name":"Photoimmunotherapy as an in situ vaccine with PD-1 blockade","route":"/ideas/idea-photoimmunotherapy-plus-pd1/"},{"id":"idea-bio2-radiotherapy-sting-fractionation","kind":"idea","name":"Pick the radiation dose that switches the immune alarm on, not off","route":"/ideas/idea-bio2-radiotherapy-sting-fractionation/"},{"id":"idea-mesothelin-car-t-regional","kind":"idea","name":"Regionally delivered mesothelin CAR-T with PD-1 blockade","route":"/ideas/idea-mesothelin-car-t-regional/"},{"id":"idea-bio2-trem2-myeloid-reprogramming","kind":"idea","name":"Reprogramme suppressive macrophages instead of trying to delete them","route":"/ideas/idea-bio2-trem2-myeloid-reprogramming/"},{"id":"idea-bio2-liver-niche-kupffer-reprogramming","kind":"idea","name":"Reprogramme the liver's own immune cells to refuse metastases","route":"/ideas/idea-bio2-liver-niche-kupffer-reprogramming/"},{"id":"idea-pdac-stromal-reprogramming-not-depletion","kind":"idea","name":"Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint","route":"/ideas/idea-pdac-stromal-reprogramming-not-depletion/"},{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/"},{"id":"idea-bio2-fmt-plus-checkpoint-phase3","kind":"idea","name":"Take faecal transplant plus immunotherapy to a definitive trial","route":"/ideas/idea-bio2-fmt-plus-checkpoint-phase3/"},{"id":"idea-bio2-fibre-diet-io-trial","kind":"idea","name":"Test a high-fibre diet as an immunotherapy adjunct","route":"/ideas/idea-bio2-fibre-diet-io-trial/"},{"id":"idea-bio2-protein-plus-training-during-io","kind":"idea","name":"Test protein and resistance training during immunotherapy","route":"/ideas/idea-bio2-protein-plus-training-during-io/"},{"id":"idea-bio2-trained-immunity-priming","kind":"idea","name":"Train the bone marrow to make better anti-tumour immune cells","route":"/ideas/idea-bio2-trained-immunity-priming/"},{"id":"idea-bio2-intracavitary-immunotherapy","kind":"idea","name":"Treat the body cavity, not the bloodstream, for surface spread","route":"/ideas/idea-bio2-intracavitary-immunotherapy/"},{"id":"idea-bio2-lymph-node-immune-priming","kind":"idea","name":"Treat the draining lymph node before removing it","route":"/ideas/idea-bio2-lymph-node-immune-priming/"},{"id":"idea-bio2-in-situ-vaccination-solid","kind":"idea","name":"Turn one tumour into a vaccine to treat all the others","route":"/ideas/idea-bio2-in-situ-vaccination-solid/"},{"id":"idea-bio2-epigenetic-priming-cold-tumours","kind":"idea","name":"Unmask hidden antigens with a short epigenetic course before immunotherapy","route":"/ideas/idea-bio2-epigenetic-priming-cold-tumours/"},{"id":"idea-bio2-hypoxia-guided-adenosine","kind":"idea","name":"Use a hypoxia scan to pick patients for adenosine-pathway drugs","route":"/ideas/idea-bio2-hypoxia-guided-adenosine/"},{"id":"idea-bio2-vascular-normalisation-window","kind":"idea","name":"Use imaging to find the window when tumour blood vessels are working properly","route":"/ideas/idea-bio2-vascular-normalisation-window/"}],"roadmap":[{"id":"immunotherapy-roadmap","kind":"roadmap","name":"Immunotherapy roadmap: Coley's toxins → checkpoint inhibitors → engineered immunity","route":"/roadmaps/immunotherapy-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"}],"collection":[{"id":"cellxgene-hca","kind":"collection","name":"CZ CELLxGENE / Human Cell Atlas","route":"/collections/cellxgene-hca/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"cytokine-therapy","kind":"technology","name":"Cytokines & engineered cytokines","route":"/technologies/cytokine-therapy/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"oncolytic-virus","kind":"technology","name":"Oncolytic viruses","route":"/technologies/oncolytic-virus/"},{"id":"neoantigen-mrna-vaccine","kind":"technology","name":"Personalised neoantigen (mRNA) vaccines","route":"/technologies/neoantigen-mrna-vaccine/"},{"id":"photoimmunotherapy","kind":"technology","name":"Photoimmunotherapy & photodynamic therapy","route":"/technologies/photoimmunotherapy/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"sting-agonist","kind":"technology","name":"STING & innate immune agonists","route":"/technologies/sting-agonist/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"cd47","kind":"target","name":"CD47","route":"/targets/cd47/"},{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"lag3","kind":"target","name":"LAG-3","route":"/targets/lag3/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"tigit","kind":"target","name":"TIGIT","route":"/targets/tigit/"}],"drug":[{"id":"adu-s100","kind":"drug","name":"ADU-S100 (MIW815)","route":"/drugs/adu-s100/"},{"id":"autogene-cevumeran","kind":"drug","name":"Autogene cevumeran","route":"/drugs/autogene-cevumeran/"},{"id":"epacadostat","kind":"drug","name":"Epacadostat","route":"/drugs/epacadostat/"},{"id":"fap-2286","kind":"drug","name":"FAP-2286 (177Lu / 68Ga)","route":"/drugs/fap-2286/"},{"id":"intismeran-autogene","kind":"drug","name":"Intismeran autogene","route":"/drugs/intismeran-autogene/"},{"id":"magrolimab","kind":"drug","name":"Magrolimab","route":"/drugs/magrolimab/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"},{"id":"tiragolumab","kind":"drug","name":"Tiragolumab","route":"/drugs/tiragolumab/"},{"id":"vusolimogene-oderparepvec","kind":"drug","name":"Vusolimogene oderparepvec","route":"/drugs/vusolimogene-oderparepvec/"}],"company":[{"id":"10x-genomics","kind":"company","name":"10x Genomics","route":"/companies/10x-genomics/"},{"id":"biontech","kind":"company","name":"BioNTech","route":"/companies/biontech/"},{"id":"moderna","kind":"company","name":"Moderna","route":"/companies/moderna/"},{"id":"replimune","kind":"company","name":"Replimune","route":"/companies/replimune/"}],"pathway":[{"id":"cgas-sting","kind":"pathway","name":"cGAS-STING innate sensing","route":"/pathways/cgas-sting/"},{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"myeloid-suppression-axis","kind":"pathway","name":"Myeloid suppression: TAMs, MDSCs & don't-eat-me signals","route":"/pathways/myeloid-suppression-axis/"},{"id":"nutrient-competition-tme","kind":"pathway","name":"Nutrient competition & metabolic immunosuppression","route":"/pathways/nutrient-competition-tme/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"term":[{"id":"abscopal-effect","kind":"term","name":"Abscopal effect","route":"/terms/abscopal-effect/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"},{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immunogenic-cell-death","kind":"term","name":"Immunogenic cell death","route":"/terms/immunogenic-cell-death/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/"}],"trial":[{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"id":"interpath-001","kind":"trial","name":"INTerpath-001 (V940-001)","route":"/trials/interpath-001/"},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"},{"id":"napoli-3","kind":"trial","name":"NAPOLI 3","route":"/trials/napoli-3/"},{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/"}],"paper":[{"id":"paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","kind":"paper","name":"Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial","route":"/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/"},{"id":"paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","kind":"paper","name":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","route":"/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/"},{"id":"paper-chen-nature","kind":"paper","name":"Elements of cancer immunity and the cancer-immune set point","route":"/key-papers/paper-chen-nature/"},{"id":"paper-haslam-jama-netw-open","kind":"paper","name":"Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs","route":"/key-papers/paper-haslam-jama-netw-open/"},{"id":"paper-antonarakis-keynote-199-pembrolizumab-jco-2020","kind":"paper","name":"KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer","route":"/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/"},{"id":"paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","kind":"paper","name":"Lung adenocarcinoma promotion by air 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personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer","route":"/key-papers/paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023/"}],"institution":[{"id":"barts-cancer-institute","kind":"institution","name":"Barts Cancer Institute / Barts Health NHS Trust","route":"/institutions/barts-cancer-institute/"},{"id":"humanitas","kind":"institution","name":"IRCCS Humanitas Research Hospital","route":"/institutions/humanitas/"},{"id":"salk-institute","kind":"institution","name":"Salk Institute Cancer Center","route":"/institutions/salk-institute/"},{"id":"sanford-burnham-prebys","kind":"institution","name":"Sanford Burnham Prebys Medical Discovery Institute","route":"/institutions/sanford-burnham-prebys/"},{"id":"sitc","kind":"institution","name":"Society for Immunotherapy of Cancer","route":"/institutions/sitc/"}]}}