Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

By K. Sakuishi, L. Apetoh, Jenna M. Sullivan, B. Blazar, V. Kuchroo, A. Anderson. Journal of Experimental Medicine, 2010

2,049 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/f0d98cc22b79d9e92f316b6b0446173e84035b07

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Citations in the corpus

Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I (2020, positive): “10d– g), which retain greater function than the most severely exhausted/dysfunctional PD1 + Tim3 + cells 26 .”
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade (2018, neutral): “5 (2D1), -CD56 PE (CMSSB), - CD3 APC-eFluor780 (SK7), -Lag-3 FITC (3DS223H), -TIGIT PE (MBSA43), -2B4 FITC (eBioDM244), -CD137 FITC (4B4), -IL-2 PE (MQ1-17H12), -TNF-α APC (MAb11), - CD26 FITC (2A6), -CXCR5 Biotin (MU5UBEE), -ICOS FITC (ISA-3), -CD38 APC (HIT2), -Eomes eFluor660 (WD1928), -T-bet PE ”
The transcription factor NFAT promotes exhaustion of activated CD8+ T cells (2015, positive): “Moreover, antibodies to PD-1 and CTLA-4 have emerged as surprisingly effective agents for cancer immunotherapy (Schietinger and Greenberg, 2014), and individual or combined blockade of TIM3, PD-1, and LAG3 with antagonist antibodies has been shown to reverse exhaustion efficiently in CD8 T cells (Bl”
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, background): “Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models [157].”
Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential (2015, background): “…that are being evaluated in pre-clinical tumor models and/or in the clinic with cancer patients includes LAG-3 (Triebel et al., 1990), TIM-3 (Sakuishi et al., 2010), and VISTA (Wang et al., 2011), whereas co-stimulatory molecules include ICOS (Fan et al., 2014), OX40 (Curti et al., 2013),…”
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. (2014, positive): “Moreover, inhibitors of the PD-L1/ PD-1 axis have been reported to generate potent antitumor activity in murine tumor models and clinical trials (23–26).”