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 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 | 0,000 | 0,000 |
| 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 | 0,000 |
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 ».