Galectins and their ligands: negative regulators of anti-tumor immunity

Abstract

Cytotoxic CD8(+) T cells are major players of anti-tumor immune responses, as their functional activity can limit tumor growth and progression. Data show that cytotoxic T cells efficiently control the proliferation of tumor cells through major histocompatibility complex class I-mediated mechanisms; nevertheless, the presence of tumor-infiltrating CD8(+) T cells in lesional tissue does not always correlate with better prognosis and increased survival of cancer patients. Similarly, adoptive transfer of tumor-specific cytotoxic T cells has only shown marginal improvement in life spans of patients with metastatic disease. In this report, we discuss experimental evidence showing that expression of tumor-derived galectins, galectin (Gal)-1, Gal-3 and Gal-9, and concomitant presence of their ligands on the surface of anti-tumor immunocytes directly compromise anti-tumor CD8(+) T cell immune responses and, perhaps, undermine the promise of adoptive CD8(+) T cell immunotherapy. Furthermore, we describe novel strategies designed to counteract Gal-1-, Gal-3- and Gal-9-mediated effects and highlight their targeting potential for creating more effective anti-tumor immune responses. We believe that Gal and their ligands represent an efficacious targeted molecular paradigm that warrants clinical evaluation.

Fig. 1

Role of Gal-1, Gal-3 and Gal-9 in Tumor Immune Escape. This illustration depicts the collaborative relationship between Gal-1, Gal-3 and Gal-9 in controlling effector CD8⁺ T cell function and promoting a tolerogenic environment for tumor growth. Gal-1 secreted at high levels by certain tumor types can induce apoptosis through binding interactions with CD7 and/or CD45 on the cell surface of effector CD8⁺ T cells [18, 74, 75]. In a similar manner, Gal-3 and Gal-9 can also induce apoptosis through binding interactions with CD7 and/or CD29 or with TIM-3, respectively [8, 10]. Alternatively, Gal-1 can theoretically trigger the synthesis of IL-10 and Th2 cytokines, whereas Gal-1, Gal-3 and Gal-9 can all suppress IFN-γ production and potentially other, yet to be described, effector cytolytic molecules [3, 12, 23, 25, 76]. These effects ultimately result in an “exhausted” phenotype, resembling the effects of PD-1 – PD-L1-mediated interactions, through binding to ligands that have yet to be fully characterized