T cell receptor sequencing of activated CD8 T cells in the blood identifies tumor-infiltrating clones that expand after PD-1 therapy and radiation in a melanoma patient

• Type of Material: Article
• Authors: Andreas Wieland, Emory University; Alice O. Kamphorst, Emory University; Nazmi Adsay, Emory University; Jonathan J Masor, Emory University; Juan Sarmiento, Emory University; Tahseen H. Nasti, Emory University; Sam Darko, National Institutes of Health; Daniel C. Douek, National Institutes of Health; Yue Xue, Emory University; Walter J Curran, Emory University; David H Lawson, Emory University; Rafi Ahmed, Emory University
• Language: English
• Date: 2018-11-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1007/s00262-018-2228-7
• Title of Journal or Parent Work: Cancer Immunology, Immunotherapy
• ISSN: 0340-7004
• Volume: 67
• Issue: 11
• Start Page: 1767
• End Page: 1776
• Grant/Funding Information: This research project was supported in part by a Winship Cancer Institute Melanoma Research Pilot Grant; and the Emory University School of Medicine Flow Cytometry Core.
• Keywords: PERIPHERAL-BLOOD; T cell repertoire; Life Sciences & Biomedicine; CANCER-PATIENTS; IMMUNE CHECKPOINT INHIBITORS; Immunotherapy; Oncology; OLDER PATIENTS; PD-1; Science & Technology; REPERTOIRE; CLINICAL-OUTCOMES; BRAIN METASTASES; Melanoma; ANTI-PD-1 THERAPY; EXPRESSION; CD8 T cells; LUNG-CANCER; Immunology
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

PD-1-targeted therapy has dramatically changed advanced cancer treatment. However, many questions remain, including specificity of T cells activated by PD-1 therapy and how peripheral blood analysis correlates to effects at tumor sites. In this study, we utilized TCR sequencing to dissect the composition of peripheral blood CD8 T cells activated upon therapy, comparing it with tumor-infiltrating lymphocytes. We report on a nonagenarian melanoma patient who showed a prominent increase in peripheral blood Ki-67 + CD8 T cells following brain stereotactic radiation and anti-PD-1 immunotherapy. Proliferating CD8 T cells exhibited an effector-like phenotype with expression of CD38, HLA-DR and Granzyme B, as well as expression of the positive costimulatory molecules CD28 and CD27. TCR sequencing of peripheral blood CD8 T cells revealed a highly oligoclonal repertoire at baseline with one clonotype accounting for 30%. However, the majority of dominant clones—including a previously identified cytomegalovirus-reactive clone—did not expand following treatment. In contrast, expanding clones were present at low frequencies in the peripheral blood but were enriched in a previously resected liver metastasis. The patient has so far remained recurrence-free for 36 months, and several CD8 T cell clones that expanded after treatment were maintained at elevated levels for at least 8 months. Our data show that even in a nonagenarian individual with oligoclonal expansion of CD8 T cells, we can identify activation of tumor-infiltrating CD8 T cell clones in peripheral blood following anti-PD-1-based immunotherapies.