Predicting response to bacillus Calmette-Guérin (BCG) in patients with carcinoma in situ of the bladder

Abstract

Purpose: Currently, there is no reliable tool to predict response to intravesical bacillus Calmette-Guérin (BCG). Based on the fact that BCG is a Th1-polarizing immunotherapy, we attempt to correlate the pretreatment immunologic tumor microenvironment (Th1 or Th2) with response to therapy.

Materials and methods: Bladder cancer patients with initial diagnosis of carcinoma in situ (Tis) were stratified based on their response to BCG treatment. A total of 38 patients met inclusion criteria (20 patients who responded and 18 patients who did not respond). Immunohistochemical (IHC) methods known to assess the type of immunologic microenvironment (Th1 vs. Th2) were performed on tumor tissue obtained at initial biopsy/resection: the level of tumor eosinophil infiltration and degranulation (Th2 response); the number of tumor-infiltrating GATA-3(+) (Th2-polarized) lymphocytes; and the number of tumor-infiltrating T-bet(+) (Th1-polarized) lymphocytes. Results obtained from these metrics were correlated with response to treatment with BCG immunotherapy.

Results: The IHC metrics of the tumor immune microenvironment prior to BCG treatment were each statistically significant predictors of responders (R) vs. nonresponders (NR). Eosinophil infiltration and degranulation was higher for R vs. NR: 1.02 ± 0.17 vs. 0.5 ± 0.12 (P = 0.01) and 1.1 ± 0.15 vs. 0.56 ± 0.15 (P = 0.04), respectively. Ratio of GATA-3(+) (Th2-polarized) lymphocytes to T-bet(+) (Th1-polarized) lymphocytes was higher for R vs. NR: 4.85 ± 0.94 vs. 0.98 ± 0.19 (P<0.001). The 3 markers were combined to create a Th2 signature biomarker, which was a statistically significant (P<0.0001) predictor of R vs. NR. All IHC markers demonstrated that a preexisting Th1 immunologic environment within the tumor was predictive of BCG failure.

Conclusion: The Th1 vs. Th2 polarization of bladder tumor immune microenvironment prior to treatment with BCG represents a prognostic metric of response to therapy. If a patient has a preexisting Th1 immunologic response within the tumor, there is no value in using a therapy intended to create a Th1 immunologic response. An algorithm integrating 3 IHC methods provided a sensitive and specific technique that may become a useful tool for pathologists and urologists to predict response to BCG in patients with carcinoma in situ of the bladder.

Keywords: Bladder cancer; Degranulation; Eosinophils; GATA-3; T-bet; Tumor immune microenvironment.