Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure.

Diego José Laderach,Daniel Compagno

doi:10.3390/cancers13184529

Abstract

Simple SummaryThis review compiles our current knowledge of one of the main pathways activated by tumors to escape immune attack. Indeed, it integrates the current understanding of how tumor-derived circulating galectins affect the elicitation of effective anti-tumor immunity. It focuses on several relevant topics: which are the main galectins produced by tumors, how soluble galectins circulate throughout biological liquids (taking a body-settled gradient concentration into account), the conditions required for the galectins’ functions to be accomplished at the tumor and tumor-distant sites, and how the physicochemical properties of the microenvironment in each tissue determine their functions. These are no mere semantic definitions as they define which functions can be performed in said tissues instead. Finally, we discuss the promising future of galectins as targets in cancer immunotherapy and some outstanding questions in the field.Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers.

Highlights

In humans, the immune system is constituted by approximately 1013 T lymphocytes at a given time [1]
This review aims to deepen our knowledge on how galectins, abundantly produced by tumors, can impact the production, activation, and effector function of antitumor T lymphocytes; some of these processes occur at anatomic sites distant from the tumor (Figure 1)
Galectin-8 provides anti-proliferative signals to pre-activated T cells [286,287]. Together with those data exposed in the lymph node chapter, these results indicate a dual role of galectin-8 in T cell function

Summary

Introduction

The immune system is constituted by approximately 1013 T lymphocytes at a given time [1]. Lymphoid homeostasis is highly dynamic, depending on the continuous production of naïve cells in central hematopoietic organs, their activation, survival, and generation of immune memory in peripheral organs Each of these processes depends on continuous biological signals that lymphocytes receive from their microenvironment [2]. Galectins are involved in the regulation of different cellular processes, among which we can mention cell differentiation, cell adhesion and migration; gene transcription and RNA splicing; and cell cycle and apoptosis [3,4]. Such biological functions depend on their lectinic properties (recognition of N-acetyllactosamine sequences displayed on the cell surface, in the extracellular matrix, or intracellular glycoconjugates) (Table 1). Membrane receptors: Neuropilin-1, VEGF-R2, integrins α1β1 and αMβ2, actin, CD43, CD3,CD4, CD2, CD7, and CD45

T Lymphocyte Regulation by Galectins at the Periphery

Galectins’ Functions in Tumor-Draining Lymph Nodes

Galectin Functions inside the Tumor

Conclusions and Future Directions