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Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy

Riyao Yang1, Linlin Sun2,3, Ching-Fei Li2

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ryang@mdanderson.org.

Nature Communications
|February 6, 2021
PubMed

Insights

Programmed cell death protein 1 (PD-1) interaction with galectin-9 (Gal-9) promotes T cell exhaustion persistence. Targeting Gal-9, combined with GITR agonists, shows synergistic antitumor activity, suggesting Gal-9 as a novel immunotherapy target.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • T cell exhaustion is critical in tumor immune evasion and immunotherapy resistance.
  • Programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are co-expressed on exhausted T cells, suggesting functional crosstalk.
  • The precise molecular mechanisms underlying PD-1/TIM-3 interactions and their impact on T cell exhaustion remain largely undefined.

Purpose of the Study:

  • To elucidate the molecular mechanism of PD-1 and TIM-3 crosstalk in T cell exhaustion.
  • To investigate the therapeutic potential of targeting the galectin-9 (Gal-9)/TIM-3 axis in cancer immunotherapy.
  • To evaluate the combination of anti-Gal-9 therapy with GITR agonistic antibodies for enhanced antitumor effects.

Main Methods:

  • Co-immunoprecipitation assays to determine protein-protein interactions.
  • Flow cytometry to analyze T cell populations and exhaustion markers.
  • In vivo tumor models to assess therapeutic efficacy of targeted antibodies.
  • Analysis of patient cancer data to correlate Gal-9 expression with prognosis.

Main Results:

  • Programmed cell death protein 1 (PD-1) binds to galectin-9 (Gal-9), inhibiting Gal-9/TIM-3-mediated T cell death and promoting exhausted T cell survival.
  • Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and regulatory T cells (Treg cells).
  • Combination therapy with anti-Gal-9 and a GITR-agonistic antibody demonstrates synergistic antitumor activity by depleting Treg cells.
  • High Gal-9 expression correlates with poor prognosis in several human cancers, and its secretion is induced by interferons.

Conclusions:

  • PD-1 plays a crucial role in maintaining the survival of exhausted T cells through interaction with Gal-9.
  • Targeting Gal-9 represents a promising strategy for cancer immunotherapy.
  • Combination therapy targeting both Gal-9 and regulatory T cells via GITR offers a synergistic approach to enhance antitumor immunity.

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