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


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.


CONCLUSIONS
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.
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ. Electronic address: nunez.rafael@mayo.edu.
Rafael
R
Nunez-Nateras
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ.
Erik P
EP
Castle
Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ.
Cheryl A
CA
Protheroe
Department of Laboratory Medicine/Pathology, Mayo Clinic Arizona, Scottsdale, AZ.
Melissa L
ML
Stanton
Department of Laboratory Medicine/Pathology, Mayo Clinic Arizona, Scottsdale, AZ.
Tolgay I
TI
Ocal
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ.
Erin N
EN
Ferrigni
Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ.
Sergei I
SI
Ochkur
Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ.
Elizabeth A
EA
Jacobsen
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ.
Yue-Xian
YX
Hou
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ.
Paul E
PE
Andrews
Department of Laboratory Medicine/Pathology, Mayo Clinic Arizona, Scottsdale, AZ.
Thomas V
TV
Colby
Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ.
Nancy A
NA
Lee
Department of Urology, Mayo Clinic Arizona, Phoenix, AZ.
James J
JJ
Lee
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000283:Administration, Intravesical; D000368:Aged; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D002278:Carcinoma in Situ / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D015550:Cell Degranulation / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D005260:Female; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007110:Immunity, Active / Q000187:drug effects / Q000276:immunology*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D011379:Prognosis; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D000098815:T-bet Transcription Factor
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D014408:Biomarkers, Tumor; D050990:GATA3 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
Bladder cancer; Degranulation; Eosinophils; GATA-3; T-bet; Tumor immune microenvironment