Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood

• Authors: Jennifer Wilkinson Carlisle, Emory University; Caroline S. Jansen, Emory University; Maria Andrea Cardenas, Emory University; Ewelina Sobierajska, Emory University; Adriana Moon Reyes, Emory University; Rachel Greenwald, Emory University; Luke Del Balzo, Emory University; Nataliya Prokhnevska, Emory University; Omer Kucuk, Emory University; Bradley Carthon, Emory University; Patrick Connor Mullane, Emory University; Adeboye Osunkoya, Emory University; Deborah Baumgarten, Emory University; Fares Hosseinzadeh, Emory University; Scott Wilkinson, National Cancer Institute; Ross Lake, National Cancer Institute; Adam G. Sowalsky, National Cancer Institute; Yuan Liu, Emory University; Viraj Master, Emory University; Mehmet Bilen, Emory University; Haydn Kissick, Emory University
• Journal Title: Journal for ImmunoTherapy of Cancer
• Volume: Volume 10, Number 7
• Publisher: BioMed Central | 2022-07-21
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1136/jitc-2022-004803
• Subjects: Health Sciences, Immunology; Health Sciences, Oncology
• Keywords: Biomarkers; Tumor; CD8-Positive T-Lymphocytes; Immunotherapy; Kidney Neoplasms; Lymphocytes; Tumor-Infiltrating

Abstract

Purpose Checkpoint therapy is now the cornerstone of treatment for patients with renal cell carcinoma (RCC) with advanced disease, but biomarkers are lacking to predict which patients will benefit. This study proposes potential immunological biomarkers that could developed for predicting therapeutic response in patients with RCC. Methods Using flow cytometry, RNA sequencing, and T-cell receptor (TCR) sequencing, we investigated changes in T cells in the peripheral blood of patients with advanced RCC after receiving immunotherapy. We used immunofluorescence (IF) imaging and flow cytometry to investigate how intratumoral T cells in patients’ tumors (resected months/years prior to receiving checkpoint therapy) predicted patient outcomes after immunotherapy. Results We found that a small proportion of CD4 and CD8 T cells in the blood activate following checkpoint therapy, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR +CD38+CD8 T cells after treatment had the best antitumor immune response and experienced clinical benefit. Using RNA sequencing, we found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR +CD38+CD8+T cells, we found that only patients who clinically benefitted had a burst of new clonotypes enter this pool of activated cells. Finally, we found that abundant T cells in the untreated tumors predicted clinical benefit to checkpoint therapy on disease progression. Conclusions Together, these data suggest that having a strong pre-existing immune response and immediate peripheral T-cell activation after checkpoint therapy is a predictor of clinical benefit in patients with RCC.