Prognostic impact of HLA‐I neoantigen‐specific CD8+ T cells in limited‐stage follicular lymphoma
Notice bibliographique
Résumé
Introduction: Follicular lymphoma (FL) is the most common indolent NHL. Recently, we demonstrated in limited and advanced stage FL (LSFL, ASFL), that patients with longer remissions had raised clonally expanded intratumoral CD8+ T cells (Tobin, JCO 2019). Durable remissions occur in ∼50% of LSFL patients whereas ASFL is incurable. However, little is known regarding the immunological features associated with this difference. We hypothesized HLA-I neoantigen (neoAg)-specific CD8+ T cells may play a role. Methods: The discovery cohort comprised 101 patients with diagnostic paraffin embedded tissue from the TROG99.03 LSFL clinical trial (MacManus, JCO 2018), in which stage I/II patients were randomized to involved field radiation (IFRT) only or combined modality therapy between 2000 and 2012 (PET from 2006). Contemporaneous validation cohorts were (a) AusLSFL: 60 PET staged, stage I FL patients from Australia (treatment miscellaneous), and (b) CanLSFL: 60 PET staged, stage I FL patients drawn principally from Canada (IFRT only). Digital gene expression (NanoString), targeted sequencing (330 genes), and germline HLA-typing was performed. Mutations observed by sequencing were used to predict neoAgs in TROG99.03 tissues using 8 algorithms (PVACseq) and filtered according to strong binding affinity to HLA-I over wild-type (TESLA consortium guidelines; Wells, Cell 2020). Results: CD8A gene expression was tested for prognostic significance. In TROG99.03, elevated intratumoral CD8A (by MaxStat) was associated with ∼2-fold improvement in PFS for all patients: HR 0.45 (CI: 0.77–0.26, p = 0.0053) and stage I only patients: HR 2.4 (CI: 1.2–4.6, p = 0.036). In keeping with a relationship between CD8+ T cell infiltration and tumor antigen presentation, raised expression of NLRC5 (a transcriptional HLA-I activator) was also associated with superior PFS: HR 0.48 (CI: 0.99–0.24, p = 0.024). CD8A significance was confirmed in both validation cohorts (whereas NLRC5 was validated in AusLSFL only). In keeping with recent IHC CD8 protein data (Los-de Vries, Bld Adv 2022), CD8A gene expression was raised in stage I LSFL vs. 68 ASFL patients treated with immunochemotherapy (p = 0.02). Mutational profiling was concordant with published LSFL data, with CREBBP and KMT2DA most frequent. NeoAg calling methods including functional assays for neoAg peptide binding were confirmed in a separate cohort of fresh FL tissues. 59% of TROG99.03 tissues had ≥1 neoantigens detected. Importantly, unsupervised hierarchical clustering showed 2-fold enrichment of samples with neoantigens among those with high vs. low HLA-I. Conclusions: Raised CD8A is associated with favorable prognosis in LSFL. Our data suggests disease control involves populations of expanded HLA-I neoAg-specific T cells. These findings have implications for novel immunotherapeutic strategies designed to increase the rate of durable remissions. The research was funded by: National Health and Medical Research Council, Australia; Leukaemia Foundation; Mater Foundation Keywords: Diagnostic and Prognostic Biomarkers, Indolent non-Hodgkin lymphoma, Microenvironment Conflicts of interests pertinent to the abstract. C. Keane Honoraria: Takeda, Roche, AZ, MSD, Beigene C. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Honoraria: BMS, Roche, Abbvie; MSD, Lilly R. Kridel Research funding: Abbvie Educational grants: Eisai M. K. Gandhi Research funding: Beigene, Janssen
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 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 | 0,001 |
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 tête enseignante, 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 ».