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A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study

GUSTAVO MARTÍN VILLOLDO1, MARÍA TERESA POMBO2, MARIANA ARIS3, JOAQUÍN CHEMI1, PABLO MANDÓ3, SUPRIYA NAGARAJU4, JUAN CAMEAN1, ADRIÁN BURIONI1, DEBORAH EGEA1, MORA AMAT5, JOSÉ LEÓN MELLADO3, JOSÉ MORDOH3, ALBERTO VILLARONGA1, MARÍA MARCELA BARRIO3,*

1 Urology Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, 1426, Argentina
2 Immunohistochemistry Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, 1426, Argentina
3 Centro de Investigaciones Oncológicas, Fundación Cáncer FUCA, Ciudad Autónoma de Buenos Aires, 1426, Argentina
4 Urology Department, MD Anderson Cancer Center, Houston, TX, 77030, USA
5 Pathology Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, 1426, Argentina

* Corresponding Author: María Marcela Barrio, email

Oncology Research 2023, 31(2), 207-220. https://doi.org/10.32604/or.2023.028163

Abstract

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk nonmuscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/ PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (p = 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (p = 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a preexisting Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.

Graphical Abstract

A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study

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APA Style
VILLOLDO, G.M., POMBO, M.T., ARIS, M., CHEMI, J., MANDÓ, P. et al. (2023). A th2-score in the tumor microenvironment as a predictive biomarker of response to bacillus calmette guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study. Oncology Research, 31(2), 207-220. https://doi.org/10.32604/or.2023.028163
Vancouver Style
VILLOLDO GM, POMBO MT, ARIS M, CHEMI J, MANDÓ P, NAGARAJU S, et al. A th2-score in the tumor microenvironment as a predictive biomarker of response to bacillus calmette guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study. Oncol Res. 2023;31(2):207-220 https://doi.org/10.32604/or.2023.028163
IEEE Style
G.M. VILLOLDO et al., "A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study," Oncol. Res., vol. 31, no. 2, pp. 207-220. 2023. https://doi.org/10.32604/or.2023.028163



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