Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials

作者：Max Kates, Andrés Matoso, Woonyoung Choi, Alexander S. Baras, Marcus J. Daniels, Kara A. Lombardo, Aaron Brant, Nina Mikkilineni, David J. McConkey, Ashish M. Kamat, Robert S. Svatek, Sima P. Porten, Joshua J. Meeks, Seth P. Lerner, Colin P. Dinney, Peter C. Black, James M. McKiernan, Chris Anderson, Charles G. Drake, Trinity J. Bivalacqua · 发表于：Clinical Cancer Research · 年份：2019 · DOI：10.1158/1078-0432.ccr-19-1920 · 被引用次数：167 · 研究领域：Bladder and Urothelial Cancer Treatments、Immune responses and vaccinations、Cancer Immunotherapy and Biomarkers

Abstract Purpose: To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). Experimental Design: Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort. Results: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretrea...