Response to azacitidine and the TIM-3 inhibitor, sabatolimab, in MDS and CMML is associated with distinct immune and antigen-presentation states
- 1Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA; Krantz Family Center for Cancer Research, Massachusetts General Hos
Abstract
Targeting the immune checkpoint TIM-3 is of interest in myeloid neoplasms, yet the hematopoietic and immune changes associated with anti-TIM-3 therapy remain poorly characterized. We used single-cell RNA sequencing to profile bone marrow (BM) and peripheral blood from patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) treated with the hypomethylating agent azacitidine combined with sabatolimab, a monoclonal antibody targeting TIM-3, and integrated Human Cell Atlas reference datasets for comparison. CITE-seq profiling showed that TIM-3 was predominantly expressed on dendritic cells and NK cells, with variable expression across other populations, including CD34 cells and CD8 T cells. At baseline, we identified a population of CD34 myeloid-biased progenitors specific to MDS/CMML samples ("HSPC-like") characterized by inflammatory gene expression programs and features of impaired differentiation. In MDS, elevated baseline HLA class II expression across hematopoietic stem and progenitor cells (HSPCs), HSPC-like cells, and multiple myeloid populations was associated with response. Consistent with this finding, trajectory analysis suggested that nonresponders bypassed HLA class II-high states during myeloid differentiation. In MDS, the presence of distinct CD8 T-cell populations and increased interferon-response programs in CD8 T and NK cells at baseline was also associated with response. In both MDS and CMML, treatment among responders was associated with contraction of BM CD8 and CD4 T-cell populations characterized by type I interferon-responsive and inflammatory programs, including IFIT1, IFIT2, and TNF, along with expansion of a distinct GZMH/IFITM1-expressing cytotoxic CD8 T-cell population. Together, these findings identify baseline antigen-presentation and immune-response programs associated with therapeutic response and reveal coordinated remodeling of myeloid and lymphoid compartments during azacitidine/sabatolimab treatment in MDS and CMML.
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BibTeX
@misc{dey2026response,
title = {{Response to azacitidine and the TIM-3 inhibitor, sabatolimab, in MDS and CMML is associated with distinct immune and antigen-presentation states}},
author = {A. Dey and N. Smith and A. Tirard and B. Arnold and T. Chan and J. Lombardi-Story and T. Casson and T. T. Behnan and S. Aguilar-Fernandez and A. T. Fathi and G. S. Hobbs and H. Hock and P. C. Amrein and P. Reeves and M. Jan and L. Bod and T. A. Graubert and A. M. Brunner and R. Narayan and A.-C. Villani},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.764360},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764360v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Response to azacitidine and the TIM-3 inhibitor, sabatolimab, in MDS and CMML is associated with distinct immune and antigen-presentation states
AU - A. Dey
AU - N. Smith
AU - A. Tirard
AU - B. Arnold
AU - T. Chan
AU - J. Lombardi-Story
AU - T. Casson
AU - T. T. Behnan
AU - S. Aguilar-Fernandez
AU - A. T. Fathi
AU - G. S. Hobbs
AU - H. Hock
AU - P. C. Amrein
AU - P. Reeves
AU - M. Jan
AU - L. Bod
AU - T. A. Graubert
AU - A. M. Brunner
AU - R. Narayan
AU - A.-C. Villani
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.764360
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.764360v1
AB - Targeting the immune checkpoint TIM-3 is of interest in myeloid neoplasms, yet the hematopoietic and immune changes associated with anti-TIM-3 therapy remain poorly characterized. We used single-cell RNA sequencing to profile bone marrow (BM) and peripheral blood from patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) treated with the hypomethylating agent azacitidine combined with sabatolimab, a monoclonal antibody targeting TIM-3, and integrated Human Cell Atlas reference datasets for comparison. CITE-seq profiling showed that TIM-3 was predominantly expressed on dendritic cells and NK cells, with variable expression across other populations, including CD34 cells and CD8 T cells. At baseline, we identified a population of CD34 myeloid-biased progenitors specific to MDS/CMML samples ("HSPC-like") characterized by inflammatory gene expression programs and features of impaired differentiation. In MDS, elevated baseline HLA class II expression across hematopoietic stem and progenitor cells (HSPCs), HSPC-like cells, and multiple myeloid populations was associated with response. Consistent with this finding, trajectory analysis suggested that nonresponders bypassed HLA class II-high states during myeloid differentiation. In MDS, the presence of distinct CD8 T-cell populations and increased interferon-response programs in CD8 T and NK cells at baseline was also associated with response. In both MDS and CMML, treatment among responders was associated with contraction of BM CD8 and CD4 T-cell populations characterized by type I interferon-responsive and inflammatory programs, including IFIT1, IFIT2, and TNF, along with expansion of a distinct GZMH/IFITM1-expressing cytotoxic CD8 T-cell population. Together, these findings identify baseline antigen-presentation and immune-response programs associated with therapeutic response and reveal coordinated remodeling of myeloid and lymphoid compartments during azacitidine/sabatolimab treatment in MDS and CMML.
ER -