RESUMO
Urothelial carcinoma (UC) is the most frequent malignancy of the urinary system and is ranked the sixth most diagnosed cancer in men worldwide. Around 70-75% of newly diagnosed UC manifests as the non-muscle invasive bladder cancer (NMIBC) subtype, which can be treated by a transurethral resection of the tumor. However, patients require life-long monitoring due to its high rate of recurrence. The current gold standard for UC diagnosis, prognosis, and disease surveillance relies on a combination of cytology and cystoscopy, which is invasive, costly, and associated with comorbidities. Hence, there is considerable interest in the development of highly specific and sensitive urinary biomarkers for the non-invasive early detection of UC. In this review, we assess the performance of current diagnostic assays for UC and highlight some of the most promising biomarkers investigated to date. We also highlight some of the recent advances in single-cell technologies that may offer a paradigm shift in the field of UC biomarker discovery and precision diagnostics.
RESUMO
Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4+ T cells, CD8+ T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8+PD-1+ T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8+PD-1- T cells and non-Treg CD4+FOXP3- T cells; but increased exhausted CD8+PD-1+ T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1+CD8+ T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.
