Abstract PR03: Genetic mechanisms of immune evasion in colorectal cancer
Notice bibliographique
Résumé
Abstract Background: Immune checkpoint blockade has shown activity in microsatellite-instability high (MSI-H) colorectal cancers (CRCs). However, despite a very high mutational and neoantigen load among virtually all MSI-H tumors, the response rate is around 40-50%. In addition, for the majority of CRCs, which are microsatellite stable (MSS), immune checkpoint inhibitors have so far proven ineffective. Thus, to better understand the genetic drivers of immune evasion in CRC, we integrated next generation sequencing data from over 1200 tumors with transcriptional and immunohistochemical measures of immune infiltration. Methods: We molecularly characterized 1,211 colorectal cancers, including 592 tumors from The Cancer Genome Atlas with whole exome sequencing (WES) and whole transcriptome (RNAseq) data and 619 cancers from two prospective cohort studies with WES and immunohistochemical (IHC) annotations. To identify driver gene alterations and their selection pressures specific to MSI-high tumors, we developed a statistical method to identify significantly mutated microsatellite tracts and we further developed a method to identify copy neutral loss of heterozygosity (CN-LOH) events. We used an established immune-gene transcriptional signature as well as IHC stains against specific subsets of immune-infiltrating cells to identify genetic events associated with immune evasion. Results: We demonstrated that WNT-signaling and immune-related genes are significantly mutated in colorectal cancer. In MSI-H CRCs, we found biallelic antigen-presentation machinery (APM) mutations in the HLA Class I genes, B2M and TAP2, in addition to recurrent mutations in NLRC5 and RFX5, which downregulated HLA Class I expression. In all CRCs, we showed that WNT-signaling activity and APC-biallelic mutations are inversely associated with both transcriptional and IHC measures of T-cell infiltration. Specifically, nuclear CTNNB1 expression was inversely correlated with overall tumor-infiltrating lymphocytes (p = 0.027), CD8+ subset of T-cells (p = 0.0019) and CD45RO+ subset of T-cells (0.0080). Meanwhile, colorectal tumors with biallelic disruptive mutations in APC had a significantly decreased activated T-cell transcriptional signature (p = 4e-12) relative to samples with no disruptive mutations in APC. We further showed that in MSS tumors, AXIN2 (a key WNT-signaling effector) super-enhancer hypomethylation, independent of the APC mutation status, was further associated with decreased T-cell activity. Conclusions: In this largest CRC genomic analysis to date, we identify genetic events that are associated with immune evasion in this disease. Specifically, we find evidence of immuno-editing in MSI-H tumors through disruptive mutations in APM. In the MSS and MSI-H subtype of CRCs, we use transcriptional and immunohistochemical orthogonal analyses to demonstrate exclusion of an effective immune infiltrate in CRC through an active WNT-signaling pathway. Our results shed light on the underlying molecular mechanisms of immune exclusion in CRC and have direct implications for novel combination immunotherapy trials for patients with this disease. This abstract is also being presented as Poster B23. Citation Format: Marios Giannakis, Catherine Grasso, Daniel Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan Nowak, Reiko Nishihara, Charles M. Connolly, Sachet Shukla, William M. Grady, David Wheeler, Catherine J. Wu, Jesse Zaretsky, Levi Garraway, Thomas Hudson, Charles Fuchs, Antoni Ribas, Riki Peters, Shuji Ogino. Genetic mechanisms of immune evasion in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR03.
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 | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».