Immune Contexture and Differentiation Features Predict Outcome in Bladder Cancer

Background: An improved risk assessment of patients with bladder cancer (BC) is important to optimize clinical management.

Objective: To identify whether immune cell subpopulations and cancer cell-intrinsic features are associated with outcome and response to first-line chemotherapy in BC.

Design, setting, and participants: Primary tumor tissue from 785 patients with BC (stage Ta-T4b) were stained using multiplex immunofluorescence (CD3, CD8, FOXP3, CD20, CD68, CD163, and MHC-I) and immunohistochemistry (pancytokeratin, CK5/6, GATA3, programmed death 1 [PD-1], and programmed death ligand 1 [PD-L1]). A digital image analysis quantified staining results within the carcinoma cell and stromal part of the tumor.

Outcome measurements and statistical analysis: Primary endpoints were progression-free survival, recurrence-free survival, and response to first-line chemotherapy. Optimal cutoff values for investigated markers were estimated using maximally selected rank statistics and receiver operating characteristic for each primary endpoint. Time-to-event analyses were performed using Cox regression analyses.

Results and limitations: Several immune subpopulations were independently associated with clinical outcomes. Especially, high PD-1 and PD-L1 expression was independently associated with an increased risk of recurrence and progression in non-muscle-invasive tumors, but with a lower risk of recurrence in muscle-invasive tumors. Furthermore, we observed a lower likelihood of response to first-line chemotherapy in patients with basal differentiation features. Finally, a model combining clinical risk factors with our most evident prognosticator improved prediction accuracy compared with clinical risk factors alone for progression in non-muscle-invasive BC and recurrence in muscle-invasive BC. The use of tissue microarrays and a long inclusion period are limitations to this study.

Conclusions: Immune cell subpopulations and cancer cell-intrinsic features are associated with different clinical outcomes in BC.

Patient summary: Immune cells play an important role in cancer development and treatment outcomes. Infiltration with specific immune cells and the presence of markers associated with immune evasion in the tumor predict clinical outcomes in bladder cancer.