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

To characterize immune cell expression among patients with Non-Muscle Invasive Bladder Cancer (NMIBC) treated with BCG.

Patients with NMIBC treated with intravesical BCG (2008-2015) were identified, and a TMA was constructed using paired pre and post-BCG bladder samples. Immunohistochemistry 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 co-localization. RNAseq 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 naive population was then validated in a separate cohort.

The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG non-responders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and non-responders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25-28% of nonresponders and 0-4% of responders (P<0.01). PD-L1+ cells in BCG nonresponders co-localized with CD8+ T-cells. Additionally BCG therapy did not increase PD-L1 gene expression (RNAseq) or protein levels (IHC). The number of pre-treatment CD4+ T-cells was very low among PD-L1+ non-responders (12%) and high among PD-L1- non-responders (50%, p<0.01). In a separate cohort of 57 NMIBC patients undergoing BCG, baseline PD-L1 staining was similar (26%).

One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Nov 11 [Epub ahead of print]

Max Kates, Andres Matoso, Woonyoung Choi, Alexander S Baras, Marcus J Daniels, Kara 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

The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine ., Pathology, Johns Hopkins University School of Medicine., Urology, Johns Hopkins University School of Medicine., Pathology, Johns Hopkins School of Medicine., The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine., Pathology, Johns Hopkins University Medical Institutions., Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medicine., Columbia University Medical Center., The Greenberg Bladder Cancer Institute, Johns Hopkins School of Medicine., Urology, The University of Texas MD Anderson Cancer Center., Urology, UT Health San Antonio., Urology, University of California, San Francisco., Department of Urology, Northwestern University Feinberg School of Medic., Urology, Baylor College of Medicine., Urology, University of Texas MD Anderson Cancer Center., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Department of Urology, Columbia University., Department of Urology, and the Columbia Center for Translational Immunology (CCTI), Columbia University Herbert Irving Comprehensive Cancer Center.