Researchers participating in the Hoosier Cancer Research Network GU16-260 study have published a correlative analysis in Cancer Discovery. The analysis, led by David A. Braun, MD, PhD, of Yale Cancer Center; Catherine J. Wu, MD, of the Dana-Farber Cancer Institute; and Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, found that the presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma.

Congratulations to all co-authors and study teams whose hard work led to this publication!

Abstract:

Immune checkpoint inhibitors (ICI) targeting the PD-1 pathway have transformed treatment of advanced renal cell carcinoma (RCC), but mechanisms underlying therapeutic response remain largely unknown. Herein, we perform transcriptomic analysis on RCC biospecimens from 102 patients enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309) to investigate determinants of response to anti-PD1 monotherapy. Through bulk analysis, we identify an enrichment of genes associated with tertiary lymphoid structures (TLS) in responding patients. Using single-cell transcriptomics and external cohort validation, we identify a population of tissue-resident (ZNF683+ SLAMF7+) exhausted CD8+ T cells enriched in patients with poor clinical outcomes. Integrating these findings, we find tumors with high TLS and low tissue-resident exhausted CD8+ T cells have superior clinical outcomes with nivolumab. Altogether, these analyses contribute to a growing understanding of how the tumor microenvironment drives ICI- resistance and propose possible therapeutic targets to rationally overcome resistance to anti-PD1 monotherapy.

Read the full article.

Authors:

Miya B. Hugaboom (Yale University), Lena V. Wirth (Yale University), Kelly Street (University of Southern California, Los Angeles), Neil Ruthen (Dana-Farber Cancer Institute), Opeyemi A. Jegede (Dana-Farber Cancer Institute), Nicholas R. Schindler (Yale University), Valisha Shah (Dana-Farber Cancer Institute), Jacob P. Zaemes (MedStar Georgetown University Hospital), Nourhan El Ahmar (Brigham and Women’s Hospital), Sayed Matar (Brigham and Women’s Hospital), Varunika Savla (Brigham and Women’s Hospital), Toni K. Choueiri (The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute), Thomas Denize (Brigham and Women’s Hospital), Destiny J. West (Brigham and Women’s Hospital), David F. McDermott (Beth Israel Deaconess Medical Center, Harvard Medical School), Elizabeth R. Plimack (Fox Chase Cancer Center), Jeffrey A. Sosman (Northwestern University Medical Center), Naomi B. Haas (University of Pennsylvania), Mark N. Stein (Columbia University), Robert Alter (Hackensack University Medical Center), Mehmet A. Bilen (Emory University Hospital), Michael E. Hurwitz (Yale University), Hans Hammers (The University of Texas Southwestern Medical Center), Sabina Signoretti (Brigham and Women’s Hospital), Michael B. Atkins (Georgetown University Medical Center), Catherine J. Wu (Dana-Farber Cancer Institute), David A. Braun (Yale University).

About Hoosier Cancer Research Network:
Hoosier Cancer Research Network conducts innovative cancer clinical trials in collaboration with more than 100 academic and community clinical research sites across the United States. Our studies are designed by cancer researchers from our member institutions. The HCRN staff includes 55 team members who work together to support all aspects of the studies we manage, from the time we receive the initial concept from a researcher through the final publication of the study results. Currently, we are supporting more than 70 clinical trials across a wide range of cancer types. Over our 40-year history, more than 10,000 participants have enrolled in our clinical trials, leading to important discoveries that help cancer patients live longer and better after their cancer diagnosis.