The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
TIM-3 restrains anti-tumour immunity by regulating inflammasome activation
Open accessAbstract
T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells1, is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8+ T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs—but not on CD4+ or CD8+ T cells—promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8+ effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1β (IL-1β) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation. Mouse genetic studies and single-cell transcriptome analysis demonstrate that TIM-3 on dendritic cells has a key role in regulating antitumour immunity via inflammasome activation and is a potential target for anticancer therapy.
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Cites
Integrating single-cell transcriptomic data across different conditions, technologies, and species
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Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
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Self-citationDefining CD8+ T cells that provide the proliferative burst after PD-1 therapy
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Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma
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Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
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Cited by
Rahim, M. K., Okholm, T. L. H., Jones, K. B., McCarthy, E. E., Liu, C. C., Yee, J. L., Tamaki, S. J., Marquez, D. M., Tenvooren, I., Wai, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.02.021 · Cited by 455
Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance
Park, J. S., Gazzaniga, F. S., Wu, M., Luthens, A. K., Gillis, J., Zheng, W., LaFleur, M. W., Johnson, S. B., Morad, G., Park, E. M., et al. (2023) · Nature · doi:10.1038/s41586-023-06026-3 · Cited by 191
Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease
Kimura, K., Subramanian, A., Yin, Z., Khalilnezhad, A., Wu, Y., He, D., Dixon, K. O., Chitta, U. K., Ding, X., Adhikari, N., et al. (2025) · Nature · doi:10.1038/s41586-025-08852-z · Cited by 85
Self-citationPhosphatidylserine binding directly regulates TIM-3 function
Smith, C. M., Li, A., Krishnamurthy, N., & Lemmon, M. A. (2021) · Biochemical Journal · doi:10.1042/bcj20210425 · Cited by 61
Metadata
- Authors
- Dixon, K. O., Tabaka, M., Schramm, M. A., Xiao, S., Tang, R., Dionne, D., Anderson, A. C., Rozenblatt-Rosen, O., Regev, A., & Kuchroo, V. K.
- Venue
- Nature
- Published
- 2021-06-09
- Volume
- 595
- Issue
- 7865
- Pages
- 101-106
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3168169234
- Cited by
- 372
- References
- 16
- FWCI
- 19.98
- Type
- journal article
- Language
- en
- Open access
- green
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