BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer
Mathieu Rouanne, … , Laurence Zitvogel, Aurélien Marabelle
Mathieu Rouanne, … , Laurence Zitvogel, Aurélien Marabelle
Published May 3, 2022
Citation Information: J Clin Invest. 2022;132(12):e145666. https://doi.org/10.1172/JCI145666.
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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Abstract

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.

Authors

Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Séverine Mouraud, Anne-Gaëlle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K. Schneider, Roman 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

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Figure 7

Two distinct mechanisms of cancer cell immune escape with opposite HLA-I dynamics steer the outcome of BCG immunotherapy.

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Two distinct mechanisms of cancer cell immune escape with opposite HLA-I...
(A) Volcano plots showing genes that were upregulated in tumors with decreased HLA-I (HLA-I– tumors; upper panel, in red) or in tumors with increased HLA-I (HLA-I+ tumors; lower panel, in blue), according to HLA-I expression at the protein level (per IHC) after BCG immunotherapy. Significantly upregulated genes of interest in each group are identified by colored dots (P < 0.05 and a log2 fold change ≥2). (B) IHC immune profiling of bladder tumor samples before and after BCG (n = 27). The density of CD8+ in CD3+ cells (percentage) and of PD-L1 expression on immune cells (percentage) is shown (paired, 2-tailed Student’s t test). Cumulative pie charts show the mean level of CD163+CD68+ cells among intratumoral macrophages (CD68+) before and after BCG (n = 27). Upper panel shows tumors with decreased HLA-I (HLA-I– tumors; in red), and lower panel shows tumors with increased HLA-I (HLA-I+ tumors; in blue). **P < 0.005 and ***P < 0.00, by paired, 2-tailed Student’s t test. (C) Number and proportion of patients who developed distant metastasis during follow-up according to the evolution of HLA-I expression in their bladder tumors before and after BCG (red, HLA-I decrease; blue, HLA-I increase). (D) Swimmer plot depicting overall survival, the time to development of resistance to BCG, and the timing of distant metastasis for individual patients with bladder cancer according to the evolution of HLA-I expression in their tumor before and after BCG (red, HLA-I decrease; blue, HLA-I increase). (E) Distant metastasis–free survival, cancer-specific survival, and OS in the cohort of patients with bladder cancer (n = 27) according to the evolution of HLA-I expression in their tumors before and after BCG (red, HLA-I decrease; blue, HLA-I increase). P values were determined by log-rank test.