期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 12, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI145666
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资金
- Fondation Foch
- Association Francaise d'Urologie (AFU)
- Fondation MSD Avenir
- Fondation Gustave Roussy
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- INSERM
- Fondation pour la Recherche Medicale (FRM)
- National Cancer Institute (NCI), NIH [U01CA247573]
- Ligue contre le Cancer
- Agence National de la Recherche (ANR)
- AMMICa
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- FRM
- Equipex OncoPheno-Screen
- European Joint Programme on Rare Diseases (EJPRD)
- European Union Horizon 2020 Projects Oncobiome and Crimson
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Institut Universitaire de France
- LabEx Immuno - Oncology [ANR-18-IDEX-0001]
- Leducq Foundation
- Mark Foundation
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- IDEX Universite de Paris [ANR-18-IDEX-0001]
- Gustave Roussy Odyssea
- [ANR-10-IAHU-01]
In patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC), two distinct patterns of immune subversion upon BCG relapse have been identified, which can predict the prognosis of the patients.
Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guerin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8(+) T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.
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