Abstract
Muscle-invasive bladder cancer (MIBC) represents approximately two-thirds of invasive urothelial bladder cancers (UBC) and has high morbidity and mortality. Men are over 3-fold more frequently affected by UBC than women. Despite intensive efforts to improve patient treatment and outcome, two-thirds of patients with UBC will have a recurrence or disease progression within 5 years. We demonstrated that the quantity and spatial distribution of stromal tumor-infiltrating lymphocytes (sTIL) within the tumor immune microenvironment (TIME) predict stages of tumor inflammation, subtypes, and patient survival and correlate with expression of immune checkpoints in an analysis of 542 patients with MIBC. High sTILs indicated an inflamed subtype with an 80% 5-year DSS, and a lack of immune infiltrates identified an uninflamed subtype with a survival rate of less than 25%. A separate immune evading phenotype with upregulated immune checkpoints associated with poor survival. Within the TIME are tertiary lymphoid structures (TLS), which can mediate antitumor activity via immune cells. High TLS amounts and close tumor distance correlated significantly with an inflamed phenotype and favorable survival. The uninflamed and evasion phenotypes showed lowest TLS numbers, farthest tumor distances, and shortest survival. High inflammation also correlated with increased neoantigen load and mutational burden. Patients treated with adjuvant chemotherapy showed a favorable prognosis, which was dependent on high sTILs. Determination of sTILs and tumor subtypes may stratify therapy success and patient survival, and considering sTILs can easily be quantified using simple morphologic parameters, like hematoxylin and eosin, sTILs can be implemented for predicting patient survival in a routine manner.
Highlights
Urothelial bladder cancer (UBC) is one of the 10th most common malignancies worldwide and the second most common cancer of the genitourinary tract [1]
High stromal tumor-infiltrating lymphocytes (sTIL) associate with increased immune cells and checkpoint gene expression Tumors within the Cancer Center Erlangen Metropol Region Nuremberg cohort (CCC-EMN) cohort with high infiltration of sTILs were characterized by dense infiltrates of CD3þ, CD8þ, CD68þ, CD56þ, PD-1þ, PD-L1þ ICs and high numbers of tertiary lymphoid structures (TLS) (Fig. 1A–C; Supplementary Fig. S1A–S1C)
This was in contrast to normal healthy bladder tissue, where significantly lower amounts of sTILs were noted (Supplementary Fig. S1A)
Summary
Urothelial bladder cancer (UBC) is one of the 10th most common malignancies worldwide and the second most common cancer of the genitourinary tract [1]. Current therapy for muscleinvasive bladder cancer (MIBC) consists of radical cystectomy, with bilateral lymphadenectomy in combination with platinumbased perioperative chemotherapy, in patients with extravesical tumors and/or lymph node metastasis [2]. MIBC is characterized by a poor 5-year survival of 40%–60% [2]. Molecular characterization of MIBC demonstrates two major phenotypes, luminal and basal tumors with significant prognostic and predictive value [3, 4]. Immunotherapeutic agents offer new therapy options for patients with metastasized UBC [5]. The FDA has approved immunotherapeutic agents targeting PD-1 or Gynecology and Obstetrics, University Hospital Erlangen, FriedrichAlexander Universit€at Erlangen-Nu€rnberg, Erlangen, Germany. The FDA has approved immunotherapeutic agents targeting PD-1 or Gynecology and Obstetrics, University Hospital Erlangen, FriedrichAlexander Universit€at Erlangen-Nu€rnberg, Erlangen, Germany. 3Department of Microbiology, Immunology, and Tropical Medicine, The George
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
