Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05-5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

Cancers. 2021 Mar 23*** epublish ***

Eileen Shiuan, Anupama Reddy, Stephanie O Dudzinski, Aaron R Lim, Ayaka Sugiura, Rachel Hongo, Kirsten Young, Xian-De Liu, Christof C Smith, Jamye O'Neal, Kimberly B Dahlman, Renee McAlister, Beiru Chen, Kristen Ruma, Nathan Roscoe, Jehovana Bender, Joolz Ward, Ju Young Kim, Christine Vaupel, Jennifer Bordeaux, Shridar Ganesan, Tina M Mayer, Gregory M Riedlinger, Benjamin G Vincent, Nancy B Davis, Scott M Haake, Jeffrey C Rathmell, Eric Jonasch, Brian I Rini, W Kimryn Rathmell, Kathryn E Beckermann

Medical Scientist Training Program, Vanderbilt University, Nashville, TN 37232, USA., Prism Bioanalytics, North Carolina Biotechnology Center, Morrisville, NC 27560, USA., Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Health Science Center, College of Medicine, The University of Tennessee, Memphis, TN 38163, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Navigate Biopharma Services, Inc., A Novartis Subsidiary, Carlsbad, CA 92008, USA., Thermo Fisher Scientific, Sacramento, CA 95605, USA., Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA., Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA., Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA.