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Conventional and PD-L1-expressing Regulatory T Cells are Enriched During BCG Therapy and may Limit its Efficacy

  • Mathieu F. Chevalier 1,
  • Anna K. Schneider 1,
  • Valerie Cesson 1,
  • Florence Dartiguenave 1,
  • Ilaria Lucca 1,
  • Patrice Jichlinski 1,
  • Denise Nardelli-Haefliger 1,
  • Laurent Derré 1
1 Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

Publication: European Urology, Volume 74, Issue 5, July 2018, Pages 540-544

The regulation of immune responses occurring during Bacillus Calmette-Guerin (BCG) therapy need to be better scrutinized in order to identify new targetable pathways for non-muscle invasive bladder cancer treatment. Immunoregulatory mechanisms have emerged as key players in various cancers. While T lymphocytes are crucial for the control of tumor growth, they often include regulatory subsets known to restrain their anti-tumor activity. In this prospective study, we assessed conventional regulatory T cells (cTregs) and PD-L1-expressing CD4 T cells (PD-L1+Tregs) levels in blood and urine of urothelial cancer (UCa) patients undergoing BCG treatment. Local cTregs were found at higher frequencies than their counterpart in the periphery and induced by bladder tumor cells in vitro. Interestingly, while circulating PD-L1+ Tregs were hardly detectable in the blood of healthy donors and UCa patients, substantial levels were found in patients’ urine. In vitro experiments suggested that BCG infection of urothelial cells could induce PD-L1+ Tregs, partially via an interferon-β-mediated mechanism. Of note, high level of Tregs in urine was associated with rapid recurrence following BCG therapy. Our findings demonstrate that T lymphocytes recruited during BCG therapy encompass a significant fraction of regulatory cells including a non-classical source of PD-L1 and reinforce treatment strategies combining BCG with PD-1/PD-L1 checkpoint inhibitors as promising approaches for non-muscle invasive bladder cancer.

Patient summary

We investigated the presence of particular immune cell types in the urine of bladder cancer patients undergoing Bacillus Calmette-Guerin (BCG) therapy. We identified a cell type that is strongly enriched in the urine after BCG instillation and that may favor tumor recurrence. This immune subpopulation might be targeted for bladder cancer treatment.

Commented by Francesco Soria

Antibodies blocking the PD-L1/PD-1 axis may, in the next future, represent a breakthrough in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC), as already happened in the advanced and metastatic settings. It has been shown that patients overexpressing PD-L1 on tumor cells or antigen-presenting cells usually have a better response to systemic immunotherapy. The aim of this prospective study was to evaluate the involvement and expression’s patterns of PD-L1+ T regulatory cells (T-regs) in 17 patients receiving intravesical Bacillus Calmette-Guerin (BCG). PD-L1+ T-regs were not clearly detectable in peripheral blood of heathy donors and urothelial cancer patients; conversely, they were found at consistently high levels in the urine of patients during BCG treatment. Interestingly, their presence was associated with worse recurrence-free survival rates after BCG.

The introduction of systemic immunotherapy has revolutionized the treatment of advanced and metastatic bladder cancer. With the promise to transfer its surprising results into the non-muscle invasive setting, immune checkpoint inhibitors are currently tested in several ongoing trials enrolling high risk NMIBC patients. Preliminary encouraging results of pembrolizumab in BCG-unresponsive patients (KEYNOTE-057) have been recently presented (complete response rate of 38.8% at three months).

The understanding of PD-L1 status in relation with BCG in NMIBC is of fundamental clinical importance. Actually, it is possible that, as in metastatic setting (i.e. immunotherapy indicated in first-line metastatic setting only in presence of PD-L1 expression), patients with a positive PD-L1 status respond better to systemic immunotherapy compared to those who not expressed PD-L1. Interestingly, in muscle-invasive bladder cancer, the level of PD-L1 expression on immune cells and not on cancer cells was found to be a predictor of response. In this study and for the first time, BCG was found to be able to induce the urinary expression of PD-L1+ T-regs, thus paving the way for therapeutic strategies combining BCG with immune checkpoint inhibitors targeting the PD-L1/PD-1 axis.