Abstract B011: Immunoediting in untreated mismatch repair deficient colorectal cancer
Notice bibliographique
Résumé
Abstract A subset of colorectal carcinomas (CRC) with high microsatellite instability (MSI-high) have been shown to respond to immune checkpoint blockade, while the much more common microsatellite stable (MSS) CRC do not usually respond to these immunotherapies. Most MSI-high tumors grow progressively despite a high mutational load, suggesting that the cancer may have developed means to escape from immune recognition, which is termed immunoediting. This immunoediting process includes three phases: an initial phase of nascent cancer cell elimination due to high immunogenicity, then a period of equilibrium with the immune response, finally leading to escape of the cancer cells that have developed genetic or epigenetic mechanisms allowing them to grow progressively in an immunocompetent host. It is likely that MSI-high cancers would go through similar processes to eventually escape from immune recognition. To better understand the differential immunoediting in MSI-high and MSS CRC, we combined tumor exome data from 592 cases from The Cancer Genome Atlas (TCGA) with previously published tumor exome data from 619 cases from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study to yield an unprecedented sample of 1,211 CRC molecularly characterized cases. The large number of samples, including a very large number of MSI-high cases (N = 179), gives us the power to identify the prevalence of the mechanisms of resistance discussed and thereby prioritize downstream efforts. We utilized the MutSigCV algorithm to identify significantly mutated genes in MSS and MSI-high tumors in the TCGA cohort (496 MSS and 75 MSI-high cases), and the NHS/HPFS cohorts (438 MSS and 104 MSI-high cases). We identified a total of 62 significantly mutated genes, of which 9 were identified in MSS tumors only, 40 in MSI-high tumors only, and 13 in both. Twenty-seven of the 53 significantly mutated genes in MSI-high were novel, likely resulting from a large increase in the number of MSI-high tumors relative to previous studies. We identified 13 significantly mutated genes with a documented role in the immune system, specifically in MSI-high tumors, a subtype shown previously to have a high level of T-cell infiltration; ZFP36L2 and B2M were significantly mutated in both MSS and MSI-high. B2M, HLA-A, and HLA-B are significantly mutated antigen presenting genes that were previously reported to be recurrently mutated in MSI-high. Eleven of the significantly mutated immune-related genes had roles in modulating diverse hematopoietic cell types and effects beyond antigen presentation; those genes include XYLT2, a dendritic cell trafficking gene; ZBTB20, a Toll-like receptor mediating immune response; RNF128, a regulator of IL2 and IL4 mediated T-cell maturation; KLF3, a gene involved in B-cell development; ZFP36L2, a gene involved in thymocyte development; CASP8, a gene involved in innate immunity; and CD58, a gene involved in the activation of both T lymphocytes and NK cells. Together, these mutations indicate positive selection for immune escape through other mechanisms beyond mutations in antigen-presenting machinery. Citation Format: Catherine Grasso, Marios Giannakis, Daniel Wells, David Wheeler, Eve Shinbrot, Syed Zaidi, Jeroen Huyghe, Milan Geybels, Stephen Salipante, Gabriel Abril-Rodriguez, Helena Escuin-Ordinas, Cristina Puig-Saus, Daniel Sanghoon Shin, Shuji Ogino, Antoni Ribas, Ulrike Peters. Immunoediting in untreated mismatch repair deficient colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B011.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».