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TIM-3+ T cells are not exhausted but activated cells in the tumor microenvironment

  • Hyun-Bae Jie
  • Jing Li
  • Raghvendra Srivastava
  • Robert L Ferris
Open Access
Poster presentation
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Keywords

Cetuximab Tumor Microenvironment Tumor Infiltrate Lymphocyte Activation Induce Cell Death Costimulatory CD137 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Although T-cell immunoglobulin mucin 3 (TIM-3) does not contain inhibitory or death signaling motifs in its cytoplasmic domain, it has been proposed to be associated with T cell suppression and/or exhaustion. However, several lines of evidence suggest that TIM-3 can stimulate T cells as a costimulatory molecule by coupling Src family tyrosine kinase Fyn and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor to TCR signaling. We examined the expression pattern and function of TIM-3 and other immune checkpoint receptors, CTLA-4 and PD-1 on tumor infiltrating lymphocytes (TIL), compared to those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNC). Here, we report that TIM-3+CD8+ TIL express higher granzyme B/perforin, more actively proliferate under anti-CD3/-CD28 stimulatory conditions, and are more resistant to activation induced cell death than TIM-3-CD8+ TIL, indicating TIM-3 can positively regulate T cell responses. Analysis of downstream signaling molecules including phosphorylated JAK/STAT-1, PD-1/SHP-2, and costimulatory CD137 in CD8+ TIL subsets supports our observation that TIM-3+CD8+ TIL are activated cells in HNC patients. However, PD-1 and CTLA-4 can negatively regulate immune responses of TIM-3+CD8+ and TIM-3+CD4+ TIL respectively. More importantly, neoadjuvant immunotherapy of HNC patients with the EGFR-specific mAb cetuximab increased both TIM-3 and PD-1 expression on CD8+ TIL, which was correlated with higher granzyme B/perforin expression in TIM-3+CD8+ TIL. Taken together, these findings suggest that TIM-3 functions as a positive regulator of activated T cells in the tumor microenvironment while CTLA-4 and PD-1 modulate the function of activated TIM-3+ TIL. We therefore suggest that TIM-3 can be used as a biomarker to indicate activation status of T cells in the tumor microenvironment depending on PD-1 co-expression, particularly in response to cancer therapy including cetuximab-based immunotherapy.

Copyright information

© Jie et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Hyun-Bae Jie
    • 1
  • Jing Li
    • 1
  • Raghvendra Srivastava
    • 1
  • Robert L Ferris
    • 1
    • 2
    • 3
  1. 1.OtolaryngologyUniversity of PittsburghPittsburghUSA
  2. 2.ImmunologyUniversity of PittsburghPittsburghUSA
  3. 3.Cancer Immunology ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA

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