Shaping the Immune Landscape in Cancer by Galectin-Driven Regulatory Pathways

Abstract

Along with the discovery of tumor-driven inflammatory pathways, there has been a considerable progress over the past 10years in understanding the mechanisms leading to cancer immunosurveillance and immunoediting. Several regulatory pathways, typically involved in immune cell homeostasis, are co-opted by cancer cells to thwart the development of effective antitumor responses. These regulatory circuits include the engagement of inhibitory checkpoint pathways (CTLA-4, PD-1/PD-L1, LAG-3 and TIM-3), secretion of immunosuppressive cytokines (TGF-β, IL-10), and expansion and/or recruitment of myeloid or lymphoid regulatory cell populations. Elucidation of these pathways has inspired the design and implementation of novel immunotherapeutic modalities, which have already generated clinical benefits in an important number of cancer patients. Galectins, a family of glycan-binding proteins widely expressed in the tumor microenvironment (TME), have emerged as key players in immune evasion programs that differentially control the fate of effector and regulatory lymphoid and myeloid cell populations. How do galectins translate glycan-containing information into cellular programs that control immune regulatory cancer networks? Here, we uncover the selective roles of individual members of the galectin family in cancer-promoting inflammation, immunosuppression, and angiogenesis. Moreover, we highlight the relevance of corresponding glycosylated ligands and counter-receptors and the emerging function of these lectins as biological liaisons connecting commensal microbiota, systemic inflammation, and distal tumor growth. Understanding the molecular and cellular components of galectin-driven regulatory circuits, the implications of different glycosylation pathways in their functions and their clinical relevance in human cancer might lead to the development of new therapeutic approaches in a broad range of tumor types.

Molecular Mechanisms Underlying the Role of Galectin-8 as a Regulator of Cancer Growth and Metastasis

“…They contribute to many hallmarks of cancer, including sustained cell proliferation, inhibition of apoptosis, evasion of immune surveillance, promotion of angiogenesis, and induction of the metastatic process (37)(38)(39)(40). They do so by modulating the interactions between tumor, endothelial, stromal, and immune cells (37)(38)(39)(40)(41)(42). Yet, in spite of the wealth of information concerning the expression of different galectins during tumor progression (37), the molecular basis for their role in cancer growth and metastasis remains incompletely understood.…”

Myriad Roles of Glycans in Biology

“…The article by Rabinovich and Conejo-Garcia [16] explores how different galectins play roles in promoting inflammation, immunosuppression, and angiogenesis in cancer progression. They further suggest that understanding the roles of galectin-driven pathways that influence tumor progression will likely lead to the development of new therapeutics that would be applicable to a wide variety of different cancers.…”

Lymphocyte-mediated Immune Regulation in Health and Disease: The Treg and γδ T Cell Co-conspiracy

“…Developing studies in tumor immunology have identified gamma-delta (γδ) T cells as functioning under a suppressive program in order to dampen anti-tumor immunity and facilitate malignant progression. γδ T cells outnumber conventional αβ CD4+ Tregs in many solid tumors such as breast and ovarian cancers, yet they remain underinvestigated (Rabinovich, Conejo-Garcia 2016). Therefore, extending our understanding of the mechanistic properties driving the suppressive nature of such cells may lead to enhanced prognostic and therapeutic benefit.…”