Recurrent IL4R Somatic Mutations in Diffuse Large B-Cell Lymphoma Lead to an Altered Gene Expression Profile and Changes in Tumor Microenvironment Composition
Notice bibliographique
Résumé
Abstract The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is an important and conserved pathway in lymphocytes which is activated by extracellular stimuli such as cytokines and growth factors. Aberrant activation of the JAK-STAT pathway is a hallmark of a variety of lymphomas which leads to increased proliferation/survival as well as immune evasion. Regarding the latter, it has been previously described that activation of the JAK-STAT signaling pathway can alter the secretome of lymphoma cells and the composition of the tumor microenvironment (TME). Specifically, our group reported PTPN1 loss-of-function as well as IL4R gain-of-function (p.I242N) mutations up-regulate the expression of the immune regulatory chemokine CCL17 through a STATs-dependent mechanism in primary mediastinal B cell lymphoma (PMBCL). Here, we assembled a cohort of 340 diffuse large B cell lymphoma (DLBCL) patients uniformly treated with R-CHOP to investigate JAK-STAT signaling mutations (targeted gene sequencing), copy number alteration (SNP arrays), gene expression (RNAseq) and TME composition (Cibersort, IHC). We confirmed the presence of mutations in SOCS1, STAT6 and 9p24 amplification with a frequency of 13.8%, 2.5%, 11.4%, respectively. Interestingly, we also identified the presence of somatic IL4R mutations in DLBCL, including the hotspot p.I242N mutation previously reported in PMBCL. Similarly to what was reported for other alterations in the JAK-STAT pathway, IL4R mutations were significantly enriched in GCB-DLBCL as compared to the ABC subtype, unclassified or double hit lymphomas with DLBCL morphology (p=0.045). Within the GCB group, patients carrying mutations in IL4R showed inferior disease-specific survival (p=0.029) and time to progression (p=0.023) after R-CHOP therapy. Mutational analysis revealed IL4R mutation being significantly concurrent together with mutations in ACTB, KLML6, MYC, STAT6, NLRC5, TNFAIP3 and mutually exclusive with EZH2 mutations (p<0.05). However, among those gene mutations, only mutations in IL4R risk-stratified patients with GCB DLBCL and showed inferior patient outcomes. Moreover, mutations in the extracellular and transmembrane domains of IL4R resulted in gain-of-function leading to constitutive activation of the JAK-STAT pathway in vitro. Gene expression analysis of primary patient samples carrying IL4R mutations displayed increased CCL17 expression (p=0.027), which positively correlated with the level of the T-regulatory marker FOXP3 by IHC (p=0.005). In addition, in silico TME composition analysis revealed a role of IL4R mutations in inducing changes in macrophage polarization. Specifically, we observed an enrichment of an M2-like macrophage phenotype in primary patient specimens carrying IL4R mutations (p=0.01) and a high M2/M1 ratio was significantly associated with inferior patient outcomes (time to progression, log rank p=0.027). In summary, our data suggest a common mechanism between PMBCL and DLBCL where aberrant JAK-STAT activation mediated by mutations in IL4R plays a significant role in altering chemokine expression profiles and TME changes. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding. Steidl:Roche: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Tioma: Research Funding; Juno Therapeutics: Consultancy.
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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 | 0,000 |
| 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) | 0,001 | 0,000 |
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 ».