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Peer-reviewedCC BY-NC-ND 4.0Cancer Immunology Research

TIM3 Blockade with Hypomethylating Therapy Restores NK Cell and Cytotoxic CD4+ T-cell Activity in Patients with AML or MDS

  • Jani Huuhtanen1,2,3,4
  • Sofia Forstén1,2,3
  • Brittany Ford1,2,3
  • Johannes Smolander1,2,3
  • Oscar Brück1,2,3
  • Sofie Lundgren1,2,3
  • Anna Kreutzman1,2
  • Olli Dufva1,2,3
  • Matti Kankainen1,2,3,5
  • Mette Ilander1,2
  • Hanna Lähteenmäki1,2,3
  • Tiina Kasanen1,2,3
11 more authors
  • Jay Klievink1,2,3
  • Judith Leitner6
  • Peter Steinberger6
  • Mika Kontro7
  • Marc R. Pelletier8
  • Harri Lähdesmäki4
  • Catherine Sabatos-Peyton8
  • Mikael L. Rinne8
  • Kimmo Porkka1,2,3,7
  • Karita Peltonen1,2,3
  • Satu Mustjoki1,2,3,9
9 affiliations
  1. 1Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland.
  2. 2Translational Immunology Research Program, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland.
  3. 3iCAN Digital Precision Cancer Medicine Flagship, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  4. 4Department of Computer Science, Aalto University, Espoo, Finland.
  5. 5Department of Medical and Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  6. 6Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria.
  7. 7Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  8. 8Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  9. 9Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
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Abstract

Occasional complete responses (CR) to immune checkpoint inhibitor therapy demonstrate that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be immunosensitive when appropriately targeted. In this study, we analyzed patients with AML/MDS (n = 14) who were treated with the anti-TIM3 sabatolimab and the hypomethylating agent decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T-cell receptor (TCR) sequencing (n = 6) and functional coculture assays. Unlike T cell–restricted CTLA4 and PD1, TIM3 was broadly expressed across natural killer (NK) cell, myeloid cell, and T-cell populations. Therapy induced the expansion of cytotoxic NK cell subsets and enhanced type I IFN signaling. Fewer than 1% of bone marrow CD8+ T cells displayed a canonical exhaustion phenotype, and treatment preferably expanded small CD8+ T-cell clones in responders. Responders exhibited greater expansion of cytotoxic CD4+ T cells and B cells, as exemplified by a patient with preexisting CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) achieving an outstanding CR lasting 23 months. More than 20% of this patient’s lymphocytes were T-LGLL cells expressing a TCR capable of recognizing autologous blasts. Overall, our results suggest that anti-TIM3 combined with decitabine engages a distinct mechanism of immune activation compared with anti–PD-1 and anti-CTLA4, preferentially expanding NK cell and CD4+ T-cell populations.

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Cite

BibTeXRIS
BibTeX
@article{huuhtanen2026tim3,
  title = {{TIM3 Blockade with Hypomethylating Therapy Restores NK Cell and Cytotoxic CD4+ T-cell Activity in Patients with AML or MDS}},
  author = {Jani Huuhtanen and Sofia Forstén and Brittany Ford and Johannes Smolander and Oscar Brück and Sofie Lundgren and Anna Kreutzman and Olli Dufva and Matti Kankainen and Mette Ilander and Hanna Lähteenmäki and Tiina Kasanen and Jay Klievink and Judith Leitner and Peter Steinberger and Mika Kontro and Marc R. Pelletier and Harri Lähdesmäki and Catherine Sabatos-Peyton and Mikael L. Rinne and Kimmo Porkka and Karita Peltonen and Satu Mustjoki},
  journal = {Cancer Immunology Research},
  year = {2026},
  month = aug,
  doi = {10.1158/2326-6066.cir-26-0160},
  url = {https://doi.org/10.1158/2326-6066.cir-26-0160},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - TIM3 Blockade with Hypomethylating Therapy Restores NK Cell and Cytotoxic CD4+ T-cell Activity in Patients with AML or MDS
AU  - Jani Huuhtanen
AU  - Sofia Forstén
AU  - Brittany Ford
AU  - Johannes Smolander
AU  - Oscar Brück
AU  - Sofie Lundgren
AU  - Anna Kreutzman
AU  - Olli Dufva
AU  - Matti Kankainen
AU  - Mette Ilander
AU  - Hanna Lähteenmäki
AU  - Tiina Kasanen
AU  - Jay Klievink
AU  - Judith Leitner
AU  - Peter Steinberger
AU  - Mika Kontro
AU  - Marc R. Pelletier
AU  - Harri Lähdesmäki
AU  - Catherine Sabatos-Peyton
AU  - Mikael L. Rinne
AU  - Kimmo Porkka
AU  - Karita Peltonen
AU  - Satu Mustjoki
PY  - 2026
DA  - 2026/08/14
JO  - Cancer Immunology Research
DO  - 10.1158/2326-6066.cir-26-0160
UR  - https://doi.org/10.1158/2326-6066.cir-26-0160
AB  - Occasional complete responses (CR) to immune checkpoint inhibitor therapy demonstrate that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be immunosensitive when appropriately targeted. In this study, we analyzed patients with AML/MDS (n = 14) who were treated with the anti-TIM3 sabatolimab and the hypomethylating agent decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T-cell receptor (TCR) sequencing (n = 6) and functional coculture assays. Unlike T cell–restricted CTLA4 and PD1, TIM3 was broadly expressed across natural killer (NK) cell, myeloid cell, and T-cell populations. Therapy induced the expansion of cytotoxic NK cell subsets and enhanced type I IFN signaling. Fewer than 1% of bone marrow CD8+ T cells displayed a canonical exhaustion phenotype, and treatment preferably expanded small CD8+ T-cell clones in responders. Responders exhibited greater expansion of cytotoxic CD4+ T cells and B cells, as exemplified by a patient with preexisting CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) achieving an outstanding CR lasting 23 months. More than 20% of this patient’s lymphocytes were T-LGLL cells expressing a TCR capable of recognizing autologous blasts. Overall, our results suggest that anti-TIM3 combined with decitabine engages a distinct mechanism of immune activation compared with anti–PD-1 and anti-CTLA4, preferentially expanding NK cell and CD4+ T-cell populations.
SN  - 2326-6066
SN  - 2326-6074
ER  -