Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

Oncotarget. 2016 Jun 28;7(26):39916-39930. doi: 10.18632/oncotarget.9537.


Although Bacillus Calmette-Guérin (BCG) is the most successful immunotherapy for high-risk non-muscle-invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. New biomarkers are important to identify patients who will benefit most from BCG during a worldwide BCG shortage. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using monoclonal antibodies to tumor-associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). Cell densities in the lamina propria without invasion, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium were calculated. Twenty-nine (72.5%) of 40 patients were classified as BCG responders after a mean follow-up of 35.3 months. A statistically significant association was observed for BCG failure with low density of CD4+ and GATA3+ T-cells, and increased expression of FOXP3+ and CD25+ regulatory T-cells (Tregs) as well as CD68+ and CD163+ TAMs. Survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with an increased count of CD4+ and GATA3+ T-cells. TAMs, Tregs and T-bet+ T-cells were inversely correlated with RFS. Thus, the tumor microenvironment seems to influence the therapeutic response to BCG, permitting an individualized treatment.

Keywords: BCG immunotherapy; bladder cancer; lymphocytes; tumor microenvironment; tumor-associated macrophages.

MeSH terms

  • Administration, Intravesical
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / chemistry
  • Antineoplastic Agents / pharmacology
  • BCG Vaccine / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • Disease-Free Survival
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / cytology*
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local
  • Pilot Projects
  • Proportional Hazards Models
  • Th2 Cells / cytology
  • Tumor Microenvironment
  • Urinary Bladder Neoplasms / immunology
  • Urinary Bladder Neoplasms / therapy*


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • BCG Vaccine
  • Biomarkers, Tumor