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

• 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
• Journal Title: Cancer Immunology, Immunotherapy
• Volume: Volume 67, Number 11
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals | 2018-11-01, Pages 1767-1776
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s00262-018-2228-7
• Subjects: Health Sciences, Oncology; Health Sciences, Immunology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Immunology; PD-1; Immunotherapy; CD8 T cells; T cell repertoire; Melanoma; IMMUNE CHECKPOINT INHIBITORS; BRAIN METASTASES; ANTI-PD-1 THERAPY; CLINICAL-OUTCOMES; PERIPHERAL-BLOOD; CANCER-PATIENTS; OLDER PATIENTS; LUNG-CANCER; REPERTOIRE; EXPRESSION

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.