Cancer Immunology, Immunotherapy

, Volume 64, Issue 7, pp 791–804 | Cite as

Two distinct effector memory cell populations of WT1 (Wilms’ tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients

  • Yoshiki Nakae
  • Yoshihiro Oka
  • Fumihiro Fujiki
  • Soyoko Morimoto
  • Toshio Kamiya
  • Satoshi Takashima
  • Jun Nakata
  • Sumiyuki Nishida
  • Hiroko Nakajima
  • Naoki Hosen
  • Akihiro Tsuboi
  • Taiichi Kyo
  • Yusuke Oji
  • Kenji Mizuguchi
  • Atsushi Kumanogoh
  • Haruo Sugiyama
Original Article

Abstract

Wilms’ tumor gene 1 (WT1) protein is a promising tumor-associated antigen for cancer immunotherapy. We have been performing WT1 peptide vaccination with good clinical responses in over 750 patients with leukemia or solid cancers. In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1 mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/or WT1 mRNA levels increased relative to the initial state within 6 months of WT1 vaccination) prior to WT1 vaccination. Cluster and principal component analyses performed using 83 genes did not discriminate between responders and non-responders prior to WT1 vaccination. However, these analyses revealed that EM subset of WT1-specific CTLs could be divided into two groups: the “activated” and “quiescent” states; in responders, EM subset of the CTLs shifted to the “quiescent” state, whereas in non-responders, those shifted to the “activated” state following WT1 vaccination. These results demonstrate for the first time the existence of two distinct EM states, each of which was characteristic of responders or non-responders, of WT1-specific CTLs in AML patients, and raises the possibility of using advanced gene-expression profile analysis to clearly discriminate between responders and non-responders prior to WT1 vaccination.

Keywords

WT1 CTL Single-cell Gene-expression profiles 

Abbreviations

AML

Acute myeloid leukemia

BM

Bone marrow

CTLs

Cytotoxic T lymphocytes

EM

Effector memory

ER

Early relapse

GO

Gene ontology

HCR

Hematological complete remission

MRD

Minimal residual disease

PB

Peripheral blood

PBMCs

Peripheral blood mononuclear cells

PCA

Principal component analysis

PC1

First principal component

PC2

Second principal component

TAA

Pan-tumor-associated antigen

WT1

Wilms’ tumor gene 1

Supplementary material

262_2015_1683_MOESM1_ESM.pdf (66 kb)
Supplementary material 1 (PDF 66 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yoshiki Nakae
    • 1
  • Yoshihiro Oka
    • 1
    • 2
    • 3
  • Fumihiro Fujiki
    • 2
  • Soyoko Morimoto
    • 2
  • Toshio Kamiya
    • 8
  • Satoshi Takashima
    • 1
  • Jun Nakata
    • 4
  • Sumiyuki Nishida
    • 1
  • Hiroko Nakajima
    • 2
  • Naoki Hosen
    • 5
  • Akihiro Tsuboi
    • 4
  • Taiichi Kyo
    • 6
  • Yusuke Oji
    • 5
  • Kenji Mizuguchi
    • 7
  • Atsushi Kumanogoh
    • 1
    • 3
  • Haruo Sugiyama
    • 8
  1. 1.Departments of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of MedicineOsaka UniversitySuitaJapan
  2. 2.Department of Cancer Immunology, Graduate School of MedicineOsaka UniversitySuitaJapan
  3. 3.Department of Immunopathology, Immunology Frontier Research Center (World Premier International Research Center)Osaka UniversitySuitaJapan
  4. 4.Department of Cancer Immunotherapy, Graduate School of MedicineOsaka UniversitySuitaJapan
  5. 5.Department of Cancer Stem Cell Biology, Graduate School of MedicineOsaka UniversitySuitaJapan
  6. 6.Department of HematologyHiroshima Red Cross and Atomic Bomb Survivor HospitalHiroshima-CityJapan
  7. 7.National Institute of Biomedical InnovationIbarakiJapan
  8. 8.Department of Functional Diagnostic Science, Graduate School of MedicineOsaka UniversitySuitaJapan

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