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

1
Medical Scientist Training Program, Vanderbilt University, Nashville, TN 37232, USA
2
Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
3
Prism Bioanalytics, North Carolina Biotechnology Center, Morrisville, NC 27560, USA
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Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA
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Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA
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Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Health Science Center, College of Medicine, The University of Tennessee, Memphis, TN 38163, USA
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Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Navigate Biopharma Services, Inc., A Novartis Subsidiary, Carlsbad, CA 92008, USA
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Thermo Fisher Scientific, Sacramento, CA 95605, USA
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Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
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Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
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Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
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Curriculum in Bioinformatics and Computational Biology, Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Nashville Veterans Affairs Medical Center, Nashville, TN 37212, USA
*
Author to whom correspondence should be addressed.
Academic Editor: José I. López
Cancers 2021, 13(6), 1475; https://doi.org/10.3390/cancers13061475
Received: 19 February 2021 / Revised: 15 March 2021 / Accepted: 16 March 2021 / Published: 23 March 2021
(This article belongs to the Collection Urological Cancer)
Immune checkpoint inhibitor (ICI) therapy has proven effective for many cancer patients, but predicting which patients with renal cell carcinoma (RCC) will respond has been challenging. We analyzed clinical characteristics and molecular parameters of a cohort of patients with RCC treated with anti-programmed death 1 (PD-1)/PD-L1 therapy to determine factors that correlate with patient outcome. We found that the composition of circulating immune cells in the blood, development of immune-related toxicities, and gene expression patterns within the tumor correlate with patient response. In addition, we see that high expression of PD-L1 and lower numbers of unique T cell clones in RCC tumors are associated with improved survival. In summary, our findings corroborate previously published work and introduce new potential factors impacting response to ICI therapy that deserve further investigation.
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. View Full-Text
Keywords: renal cell carcinoma; PD-1; PD-L1; biomarkers; immune checkpoint inhibitors renal cell carcinoma; PD-1; PD-L1; biomarkers; immune checkpoint inhibitors
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Figure 1

MDPI and ACS Style

Shiuan, E.; Reddy, A.; Dudzinski, S.O.; Lim, A.R.; Sugiura, A.; Hongo, R.; Young, K.; Liu, X.-D.; Smith, C.C.; O’Neal, J.; Dahlman, K.B.; McAlister, R.; Chen, B.; Ruma, K.; Roscoe, N.; Bender, J.; Ward, J.; Kim, J.Y.; Vaupel, C.; Bordeaux, J.; Ganesan, S.; Mayer, T.M.; Riedlinger, G.M.; Vincent, B.G.; Davis, N.B.; Haake, S.M.; Rathmell, J.C.; Jonasch, E.; Rini, B.I.; Rathmell, W.K.; Beckermann, K.E. Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma. Cancers 2021, 13, 1475. https://doi.org/10.3390/cancers13061475

AMA Style

Shiuan E, Reddy A, Dudzinski SO, Lim AR, Sugiura A, Hongo R, Young K, Liu X-D, Smith CC, O’Neal J, Dahlman KB, McAlister R, Chen B, Ruma K, Roscoe N, Bender J, Ward J, Kim JY, Vaupel C, Bordeaux J, Ganesan S, Mayer TM, Riedlinger GM, Vincent BG, Davis NB, Haake SM, Rathmell JC, Jonasch E, Rini BI, Rathmell WK, Beckermann KE. Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma. Cancers. 2021; 13(6):1475. https://doi.org/10.3390/cancers13061475

Chicago/Turabian Style

Shiuan, Eileen; Reddy, Anupama; Dudzinski, Stephanie O.; Lim, Aaron R.; Sugiura, Ayaka; Hongo, Rachel; Young, Kirsten; Liu, Xian-De; Smith, Christof C.; O’Neal, Jamye; Dahlman, Kimberly B.; McAlister, Renee; Chen, Beiru; Ruma, Kristen; Roscoe, Nathan; Bender, Jehovana; Ward, Joolz; Kim, Ju Y.; Vaupel, Christine; Bordeaux, Jennifer; Ganesan, Shridar; Mayer, Tina M.; Riedlinger, Gregory M.; Vincent, Benjamin G.; Davis, Nancy B.; Haake, Scott M.; Rathmell, Jeffrey C.; Jonasch, Eric; Rini, Brian I.; Rathmell, W. K.; Beckermann, Kathryn E. 2021. "Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma" Cancers 13, no. 6: 1475. https://doi.org/10.3390/cancers13061475

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