Abstract PR-02: Loss of tumor-intrinsic type I IFN facilitates and predicts bone-metastatic progression in advanced prostate cancer and drives radiotherapeutic resistance
Notice bibliographique
Résumé
Abstract Background: Bone metastases occur in up to 90% of men with castration-resistant prostate cancer (CRPC) and are invariably fatal. A "cold" tumor microenvironment has been implicated in the failure of conventional and targeted therapies to improve long-term survival in metastatic disease. Yet, studies interrogating the bone metastatic niche for candidate drivers of therapeutic resistance are lacking, as are real-world strategies to advance precision approaches that reduce patient mortality. Here we define explicit and previously undisclosed features of the tumor-immune landscape that shape CRPC progression to bone and reveal key predictors of resistance to radioligand therapy (RLT). Methods: We performed in-depth single cell and digital spatial profiling linked to transcriptomic analysis of >230 prostate cancer patients from 6 independent cohorts spanning >100 tissues and PDX from adenocarcinomas (non-metastatic and metastatic) to lymph node (LN) and bone metastases, with >32 matched tumors. Results: Bone metastases show a significant site-specific loss of type I interferon (IFN-I) signaling and antigen presentation markers (HLA-I) compared to LN and primary tumors. Tumor-intrinsic (TI) IFN-I signaling is predictive of bone metastasis (HR=0.92, p=0.04) while tumor cell HLA-I is predictive of bone metastasis-free survival (HR=0.97, p=0.03) and biochemical recurrence (HR=0.97, p=0.009). Bone metastasis is correlated with robust suppression of both TI IFN-I signaling and HLA-I (r=0.79, p<0.0001) compared to metastatic and non-metastatic primaries. Metastasis is associated with increased Treg, while tumor-excluded memory T cells are only predictive of better bone metastasis-free survival when active TI IFN-I is intact. A bone-specific enrichment of tumor-infiltrating M2 macrophages is observed yet is not prognostic. Similarly, a bone-specific loss of HLA-II and dendritic cell activation is evidenced yet holds no predictive value. Notably, we identified a bone-specific loss of >15 IFN-I regulated druggable targets compared to matched adenocarcinomas concurrent to a bone-specific TI increase in B7-H3, validated in PDX and 3 independent cohorts. Systemic immune analysis in men receiving PSMA-targeted RLT reveal that radiographic progression in CRPC can be predicted by IFN-I driven antigen presentation markers in novel immune subsets as early as cycle 2 of treatment. Conclusion: We reveal the first in-depth profiling of the bone metastatic landscape in CRPC and identify TI IFN-I biomarkers as superior to the quantitation and characterization of tumor infiltrating immune cells to predict risk of bone metastasis. Our findings suggest the loss of tumor immunogenicity in CRPC is a critical mediator of bone-specific progression, drives therapeutic resistance and underpins response to targeted RLT. Here, we highlight the utility of TI IFN-I markers to predict CRPC progression to bone and discuss novel points of intervention to limit autoimmune responses to RLT and IFN-activating therapies that may improve survival for men with a lethal stage of disease. Citation Format: Katie L. Owen, Linden J. Gearing, Chris Hovens, Shahneen Sandhu, Michael Hofman, Belinda S. Parker, Luc Furic. Loss of tumor-intrinsic type I IFN facilitates and predicts bone-metastatic progression in advanced prostate cancer and drives radiotherapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-02.
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 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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,002 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 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 ».