TIM3 blockade with hypomethylating therapy restores NK-cell and cytotoxic CD4+ T-cell activity in patients with AML or MDS.

Authors

Jani Huuhtanen, Sofia Forstén, Brittany Ford, Johannes Smolander, Oscar Brück, Sofie Lundgren, Anna Kreutzman, Olli Dufva, Matti Kankainen, Mette Ilander, Hanna Lähteenmäki, Tiina Kasanen, Jay Klievink, Judith Leitner, Peter Steinberger, Mika Kontro, Marc R Pelletier, Harri Lähdesmäki, Catherine Sabatos-Peyton, Mikael L Rinne, Kimmo Porkka, Karita Peltonen, Satu Mustjoki

Published in

Cancer immunology research. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

Occasional complete responses to immune checkpoint inhibitor therapy demonstrate that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be immune-sensitive when appropriately targeted. Here, we analyzed AML/MDS patients (n=14) 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 co-culture 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 expansion of cytotoxic NK-cell subsets and enhanced type I interferon 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 pre-existing CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) achieving an outstanding complete response lasting 23 months. Over 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 to anti-PD1 and anti-CTLA4, preferentially expanding NK-cell and CD4+ T-cell populations.

PMID:
42599272
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.