Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune Evasion and Immunotherapy Resistance.
Cancer Res
; 83(21): 3562-3576, 2023 11 01.
Article
en En
| MEDLINE
| ID: mdl-37578274
ABSTRACT
Parkin is an E3 ubiquitin ligase, which plays a key role in the development of Parkinson disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth, which was associated with poor tumor antigen presentation and limited antitumor CD8+ T-cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced Akt activation. Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from patients with clear cell renal cell carcinoma indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer. SIGNIFICANCE:
Parkin prevents immune evasion by regulating tumor antigen processing and presentation through the PTEN/Akt network, which has important implications for immunotherapy treatments in patients with Parkin-deficient tumors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Presentación de Antígeno
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2023
Tipo del documento:
Article