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.

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

“…The authors hypothesized that adding BCG to activate intratumoral Th1 immune response is unlikely to increase a Th1-activated cancer microenvironment [17]. Our results are in line with the observations made by Nunez-Nateras et al [17]. We registered a positive association between an increased GATA3/T-bet ratio and a prolonged recurrence-free survival.…”

“…Interestingly, a preexisting Th1 tumor microenvironment in patients with primary CIS was predictive of BCG failure in a study by Nunez-Nateras et al [17]. The authors hypothesized that adding BCG to activate intratumoral Th1 immune response is unlikely to increase a Th1-activated cancer microenvironment [17]. Our results are in line with the observations made by Nunez-Nateras et al [17].…”

“…Our results show that an increased intratumoral CD4+ T-cell population was significantly associated with BCG response (Figure 4A) and longer RFS (Figure 5A). Interestingly, a preexisting Th1 tumor microenvironment in patients with primary CIS was predictive of BCG failure in a study by Nunez-Nateras et al [17]. The authors hypothesized that adding BCG to activate intratumoral Th1 immune response is unlikely to increase a Th1-activated cancer microenvironment [17].…”

“…Several trials confirmed a significant increase of Th1-induced urinary cytokines during treatment with intravesical BCG [14–16]. Moreover, pre-therapy levels of Th1/Th2 and tumor-associated macrophage (TAM) polarization of the tumor microenvironment appear to influence BCG response [17–18]. …”

Re: Prognostic Factors and Risk Groups in T1G3 Non–Muscle-invasive Bladder Cancer Patients Initially Treated with Bacillus Calmette-Guérin: Results of a Retrospective Multicenter Study of 2451 Patients

“…Biological markers of progression or assessment of immunologic response may hold keys to identifying patients for whom BCG may not be the best option. A recent study evaluated the immunologic tumor microenvironment (Th1 or Th2) and its impact on response to therapy [5], and more such studies are needed. Finally, we still lack adequate intravesical therapies for tumors that do not respond to BCG so that we can avoid cystectomy in those who do not have progression.…”