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© Emmanuel Lemichez
Microscopy image showing the formation of large tunnels in a blood vessel endothelial cell induced by a group of bacterial toxins
Publication : The Journal of clinical investigation

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in The Journal of clinical investigation - 15 Jun 2022

Rouanne M, Adam J, Radulescu C, Letourneur D, Bredel D, Mouraud S, Goubet AG, Leduc M, Chen N, Tan TZ, Signolle N, Bigorgne A, Dussiot M, Tselikas L, Susini S, Danlos FX, Schneider AK, Chabanon R, Vacher S, Bièche I, Lebret T, Allory Y, Soria JC, Arpaia N, Kroemer G, Kepp O, Thiery JP, Zitvogel L, Marabelle A,

Link to Pubmed [PMID] – 35503263

Link to DOI – e14566610.1172/JCI145666

J Clin Invest 2022 Jun; 132(12):

Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (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.

https://pubmed.ncbi.nlm.nih.gov/35503263