Patients with high-risk non muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice in order to stratify future urothelial cancer patient treatment strategies.
The Journal of clinical investigation. 2022 May 03 [Epub ahead of print]
Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Severine Mouraud, Anne-Gaelle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie E Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K Schneider, Roman M Chabanon, Sophie Vacher, Ivan Bièche, Thierry Lebret, Yves Allory, Jean-Charles Soria, Nicholas Arpaia, Guido Kroemer, Oliver Kepp, Jean Paul Thiery, Laurence Zitvogel, Aurélien Marabelle
INSERM U1015, Gustave Roussy, Villejuif, France., Inserm U1186, Gustave Roussy, Villejuif, France., Department of Pathology, Hopital Foch, Suresnes, France., Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France., Department of Microbiology and Immunology, Columbia University, New York City, United States Minor Outlying Islands., Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., INSERM Unit U981, Gustave Roussy, Villejuif, France., INSERM U1163, University of Paris, Paris, France., Department of Pathology, Saint Joesph Hospital, Paris, France., Institute of Cancer Research, London, United Kingdom., Department of Genetics, Pharmacogenomics Unit, Institut Curie, Paris, France., Department of Urology, Hospital Foch, Suresnes, France., Department of Pathology, Hospital Foch, Suresnes, France., Department of Medicine, Gustave Roussy, Villejuif, France., National Laboratory, Guangzhou Laboratory, Guangzhou, China., Department of Therapeutic Innovation and Early Trials, Gustave Roussy, Villejuif, France.