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Author Notes:

Rafi Ahmed, Professor, Director of Emory Vaccine Center, 1510 Clifton Road, Rm G209, Atlanta, GA 30322, USA, Phone: 404-727-4700. rahmed@emory.edu,

Andreas Wieland and Alice O. Kamphorst performed experiments, analyzed data, and wrote the manuscript together with David H. Lawson and Rafi Ahmed; Tahseen H. Nasti performed experiments; Nazmi Volkan Adsay, Sam Darko, Daniel C. Douek, and Yue Xue analyzed data; Jonathan J. Masor, Juan Sarmiento, Walter J. Curran, David H. Lawson were involved in patient care and sample collection; All authors were involved in manuscript editing.

We thank Winship Cancer Institute personnel involved in this patient’s care and sample collection; with special thanks to Cabell Pietras.

We thank Patrick Raber (Adaptive Biotechnologies) for his assistance during TCR analysis.

Rafi Ahmed is an inventor on patents held by Emory University that cover the topic of PD-1–directed immunotherapy; All other authors declare no potential conflicts of interest.

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Research Funding:

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:

  • 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

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

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Journal Title:

Cancer Immunology, Immunotherapy

Volume:

Volume 67, Number 11

Publisher:

, Pages 1767-1776

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

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