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The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

Inna M Yasinska1, Svetlana S Sakhnevych1, Ludmila Pavlova2

  • 1Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, United Kingdom.

Frontiers in Immunology
|July 30, 2019
PubMed

Insights

Human cancer cells, including breast cancer, utilize the Tim-3 and galectin-9 pathway for immune evasion. This pathway, involving latrophilin 1 and FLRT3, protects cancer cells from immune attack.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Human cancer cells employ molecular mechanisms to evade immune surveillance, facilitating disease progression.
  • The Tim-3 (T-cell immunoglobulin and mucin-domain containing-3) and galectin-9 pathway was previously implicated in immune escape for acute myeloid leukemia (AML) cells.
  • Cancer cells utilize neuronal receptors like latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3) to activate signaling pathways.

Purpose of the Study:

  • To investigate the involvement of the Tim-3-galectin-9 pathway in the immune escape of various human cancer types.
  • To determine if breast tumors exhibit altered expression of Tim-3, galectin-9, LPHN isoforms, and FLRT3.
  • To assess the functional role of surface-expressed galectin-9 in protecting cancer cells from cytotoxic T cells.

Main Methods:

  • Comparative analysis of Tim-3 and galectin-9 expression in breast tumor tissues versus healthy breast tissues.
  • Detection of LPHN isoforms (LPHN1, LPHN2, LPHN3) and FLRT3 expression in breast tumor cells.
  • Assessment of galectin-9 translocation to the cell surface and its effect on breast carcinoma cell survival against cytotoxic T cells.
  • Screening of diverse cancer cell lines (brain, colorectal, kidney, liver, prostate, lung, skin, blood/mast cell) for Tim-3 and galectin-9 expression.

Main Results:

  • Breast tumors showed significantly higher co-localized expression of galectin-9 and Tim-3 compared to healthy tissues.
  • Increased expression of LPHN2, LPHN3, and FLRT3 was observed in breast tumor cells.
  • Activation of the pathway led to galectin-9 translocation to the tumor cell surface, enhancing protection against cytotoxic T cell-mediated death.
  • Tim-3 and galectin-9 were detected in a wide range of cancer cell lines, with most expressing LPHN isoforms and FLRT3.

Conclusions:

  • The Tim-3-galectin-9 pathway is utilized by a broad spectrum of human cancer cells for immune evasion.
  • This pathway, potentially involving LPHN and FLRT3, plays a role in preventing anti-tumor immunity across various cancer types.
  • Targeting the Tim-3-galectin-9 pathway may offer a therapeutic strategy to enhance anti-cancer immune responses.
Keywords:
TIM-3breast cancergalectin-9immune evasionimmune surveillance

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