Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Open accessAbstract
The immune response plays an important role in staving off cancer; however, mechanisms of immunosuppression hinder productive anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1–PD-1L interactions has been shown to partially restore T cell function. We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. All Tim-3+ TILs coexpress PD-1, and Tim-3+PD-1+ TILs represent the predominant fraction of T cells infiltrating tumors. Tim-3+PD-1+ TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.
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Tim-3, LAG-3, and BTLA are co-expressed with PD-1, and this co-expression strongly correlates with immune dysfunction in cancer patients.
“In the course of defining exhausted PD-1+ T cells, T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) [39,41], lymphocyte-activation gene (LAG)-3 [38], and the B and T-cell lymphocyte attenuator (BTLA, CD272) [42,43] were found to be co-expressed with PD-1, and the co-expression has been strongly correlated with immune dysfunction in patients with cancer.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [39]
T cells co-expressing these surface molecules show significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.
“In these studies, T cells co-expressing these surface molecules show a significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [39]
Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models.
“Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models [157].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [157]
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- Authors
- Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Center for Neurological Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 1
- University of Minnesota (US)
- Corresponding author
- Kuchroo, Vijay K.
- Anderson, Ana C.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-09-06
- Volume
- 207
- Issue
- 10
- Pages
- 2187-2194
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2947065
- OpenAlex
- W2107598346
- Cited by
- 2,072
- References
- 31
- Citations by year
- 2026: 92 · 2025: 137 · 2024: 184 · 2023: 165 · 2022: 165 · 2021: 177 · 2020: 171 · 2019: 156 · 2018: 147 · 2017: 159 · 2016: 137 · 2015: 143 · 2014: 68 · 2013: 69 · 2012: 64
- FWCI
- 27.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL056067, HL 56067, R37HL056067)
- National Cancer Institute (CA72 669, R01CA072669, P01CA065493)
- National Institute of Allergy and Infectious Diseases (AI 056299, P01AI073748, AI73748, P01AI056299)
- National Institute of Neurological Disorders and Stroke (K01NS054096, R01NS030843, NS038037, R29NS030843, NS030843, NS045937, P01NS038037, R37NS030843, NS054096, R01NS045937)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- TIM-3, PD-1, T cell exhaustion, tumor-infiltrating lymphocytes, antitumor immunity, immune checkpoint blockade, CD8+ T cells, combination immunotherapy, tumor immunosuppression, solid tumors
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Antigens, Surface, Immune Tolerance, Interferon-gamma, Interleukin-2, Lymphocyte Activation, Neoplasms, Experimental, Receptors, Virus, Tumor Necrosis Factor-alpha, Signal Transduction, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Apoptosis Regulatory Proteins, Mice, Molecular Targeted Therapy, Programmed Cell Death 1 Receptor
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