Open Access

ARTICLE

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

by 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 BARRIO^3,*

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,

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

Received 08 December 2022; Accepted 15 February 2023; Issue published 10 April 2023

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.

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