June 22, 2024

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What is the role of Galectin in tumor immunity?

What is the role of Galectin in tumor immunity?



 

What is the role of Galectin in tumor immunity?

Since the approval of the immune checkpoint inhibitor ( ICI ) ipilimumab in 2011, tumor immunotherapy has been a game-changer in cancer treatment.

Clinical practice has shown that anti-tumor T cell-mediated immunity can improve the prognosis of cancer patients.

However, tumor cells can escape immune attack by activating a variety of immune suppression mechanisms, so the number of people who can benefit from immune checkpoint inhibitors is still limited.

 

Galectin-1, -3, -7, -8 and -9 produced by tumors are one of the main molecular mechanisms for tumors to escape immune control.

These galectins affect different steps in the establishment of an antitumor immune response.

Galectins are involved in the regulation of diverse cellular processes, including cell differentiation, cell adhesion and migration, gene transcription and RNA splicing, cell cycle and apoptosis.

 

Galectins play an important role in controlling the properties of the tumor microenvironment.

Tumor-associated hypoxia and inflammation lead to dysregulated galectin expression, thus, elevated levels of these galectins are detected in the serum of cancer patients, and their expression in the tumor microenvironment often predicts the clinical prognosis of patients poor.

Therefore, it is necessary for us to conduct an in-depth study on the mechanism by which tumor-derived galectins affect the production and function of anti-tumor T lymphocytes. This knowledge can help us design more effective immunotherapies to treat human cancers.

 

 

What is the role of Galectin in tumor immunity?

 


The effect of Galectin on thymus T cells


Physiologically, galectin-1 is detected in thymic epithelial cells, endothelial cells and dendritic cells, as well as macrophages.

From a functional point of view, Galectin-1 induces thymocyte apoptosis. Highly proliferating immature CD4+CD8+ double-positive thymocytes are the main target of Galectin-1-induced cell death.

 

Galectin-3 was detected in epithelial cells and phagocytes of the medulla, and in small amounts in the cortical regions of the thymus. It should be noted that Galectin-3 has opposite effects on cells, depending on its extracellular or intracellular localization. Like Galectin-1, extracellular Galectin-3 induces thymocyte apoptosis.

However, Galectin-3 preferentially targets a different subset of cells ( CD4-CD8-double-negative thymocytes ). Furthermore, the pro-apoptotic effect of extracellular galectin-3 is opposite to the anti-apoptotic function of intracellular galectin-3. Intracellular Galectin-3 blocks Galectin-1-mediated apoptosis, implying that the two galectin members are closely related in the control of thymocyte apoptosis.

 

Galectin-9 was detected in epithelial cells throughout the thymus, but it was more abundant in the medulla compared with the cortical regions of the thymus. Likewise, Galectin-9 has its specificity compared to other galectins.

Galectin-9 induces cell death in all thymus subpopulations, and thymocyte apoptosis induced by Galectin-9 involves receptors different from those used by Galectin-1 and -3. Although the relevant receptors are not yet known, CD44 may be a potential candidate receptor.

 

Galectin-8 is also present in the thymus, but in contrast to Galectin-1, -3 and -9, it is not detected in thymic epithelial cells.

This galectin induces apoptosis in CD4+CD8+ double-positive thymocytes through a mechanism that at least in part involves activation of a caspase-mediated pathway.

 

In summary, existing studies have shown that galectins act as pro-apoptotic factors for thymocytes under physiological conditions.

After tumorigenesis, the galectin produced in large quantities by the tumor may change the types of T lymphocytes exported from the thymus to the periphery.

 

 


The role of Galectin in tumor-draining lymph nodes


The first stage of lymphocyte activation occurs in the draining lymph nodes, where a specific clonal expansion process takes place.

Tumor-derived galectins reach this site as soluble proteins through the blood and lymphatic vessels, and once in the lymph nodes, galectins affect early lymphocyte activation processes.

 

Galectin-1 plays a major regulatory role in the homing of naive lymphocytes to lymph nodes.

Thus, tumor-derived Galectin-1 reduces the influx of naive T cells into draining lymph nodes, thereby reducing T cell activation and clonal expansion. Furthermore, genome-wide functional analysis revealed that Galectin-1 is one of the master regulators of lymphatic endothelial cell function.

Galectin-1 has important effects on how tumor-derived antigens and antigen-presenting cells travel through lymphatic vessels to draining lymph nodes, and Galectin-1 inhibits the migration of immunogenic dendritic cells through the extracellular matrix and across lymphatic endothelial cells.

 

Galectin-3 has a marked effect on the activation of antitumor lymphocytes that occurs in draining lymph nodes. Recent studies have shown that tumor galectin-3 is a potent inhibitory checkpoint that suppresses lymphocyte proliferation in the prostate cancer microenvironment.

Furthermore, downregulation of galectin-3 is a prerequisite for optimal activation of lymphocytes when dendritic cell vaccines are used in prostate cancer.

 

Galectin-3 regulates the interaction between T cells and antigen-presenting cells. First, galectin-3-deficient immature dendritic cells have defective motility properties.

Thus, galectin-3 has a direct role in the induction of antitumor immune responses by controlling the migration of dendritic cells from peripheral tissues, including tumors, to draining lymph nodes.

Furthermore, this particular galectin also contributes to dendritic cell homeostasis, as an increased number of plasmacytoid dendritic cells was observed in galectin-3-deficient mice. Interestingly, plasmacytoid dendritic cells outperformed conventional cells in activating antitumor CD8+ T lymphocytes.

 

Galectin-3 also has a direct effect on T lymphocytes. Galectin-3 regulates the formation of immune synapses, restricts TCR motility, enhances TCR downregulation, inhibits early TCR signaling pathways, and controls cytokine production.

 

Currently, few studies have evaluated the role of galectin-8 in antitumor immune activation.

Existing studies have shown that galectin-8 promotes all antigen presentation steps of dendritic cells from antigen binding, internalization, processing to maturation.

Furthermore, recombinant galectin-8 increased the differentiation of CTLA-4+IL-10+CD103+ Tregs through activation of TGF-β and sustained IL-2 receptor signaling.

Tumors can use this strategy to block the immune function of draining lymph nodes. In conclusion, little is known about the biological functions of galectin-8 in cancerous lymph nodes.

 

A number of studies have shown that galectin-9 has apparently opposite roles in immune regulation.

During the activation of antitumor-specific responses, exogenous galectin-9 modulates antigen presentation, promotes differentiation of plasmacytoid dendritic cells, maturation of dendritic cells and a Th1-polarized microenvironment.

Furthermore, galectin-9 is recruited to immune synapses upon T cell activation, promoting proximal TCR signaling.

These results suggest that galectin-9 has a positive regulatory effect on T cell activation and expansion.

 

On the other hand, Galectin-9 promotes immune regulation, which can enhance the expansion and suppression phenotype of iTreg. In addition, galectin-9 also promotes the function of CD11b+Ly-6G+ myeloid suppressor cells through the interaction with Tim-3 receptor.

 

 


The role of Galectin in tumor


For galectin-1, experimental evidence suggests that tumor-derived galectin-1 plays an important role in promoting tumor growth and distant metastasis.

This mechanism remains to be explored, however, it is undeniable that the tumor-promoting effect of galectin-1 requires the active involvement of the immune system.

In fact, in immunodeficient mice, the growth of tumors expressing or not expressing galectin-1 was not significantly different, clearly indicating that the immune system is the main target of tumor galectin-1. In addition, CD4 and CD8+ T lymphocytes may be involved in the effect of galectin-1.

 

Tumor galectin-3 is another potent regulator of the effector properties of lymphocytes at the tumor site First, T cell recruitment to tumors requires an IFN-γ-induced gradient of the chemokine CXCL9/10. Galecti-3 in the extracellular matrix of tumors has been shown to prevent the generation of chemokine gradients.

 

In addition to regulating T cell migration, galectin-3 also controls effector function.

Galectin-3 reduces lymphocyte effector function through TCR downregulation, thereby converting T-infiltrating lymphocytes ( TILs ) into dysfunctional cells. CD8+ TILs that bind galectin-3 co-express LAG-3 and PD-1 in the tumor microenvironment, suggesting a central role for LAG-3 in galectin-3-mediated suppression of lymphocyte antitumor effector function.

In addition to direct effects on effector T cells, galectin-3 also attracts macrophages to tumors and promotes their M2 differentiation. Taken together, these studies suggest that galectin-3 plays a central role in tumors that evade antitumor effector functions.

 

Galectin-7 can be detected in several types of tumors, and overall, higher galectin-7 expression in tumors is a negative prognostic factor for survival in cancer patients. Galectin-7 may play a role in tumor microenvironment and immune surveillance.

Galectin-7 can be detected in tumor-associated macrophages, and the functional impact of galectin-7 on tumor-associated macrophages is still unclear.

On the other hand, recombinant galectin-7 induces apoptosis of human peripheral T cells, and besides controlling the survival of activated T cells, galectin-7 can also be used by tumors to downregulate cytokines produced by T cells.

In conclusion, galectin-7 plays an important role in the function and survival of immune cells and should be considered as a target for immunotherapy.

 

Currently, no studies have evaluated the effect of tumor galectin-8 on the generation of specific and protective immune responses. Most studies have focused on the role of this protein in tumor metastasis and angiogenesis.

 

Conflicting results have been observed in several studies evaluating the prognostic value of galectin-9 expression in solid tumors.

Several studies have found that Galectin-9 is a positive prognostic biomarker in patients with certain types of cancer, and this positive correlation between galectin-9 expression and overall survival may be related to galectin-9 inhibiting metastasis and inducing apoptosis, by Induction of a more effective anti-tumor immune response in lymph nodes.

 

However, as tumors develop into a chronic disease, galectin-9 expression correlates with poor prognosis and is often associated with immune evasion.

Intratumoral CD103+ dendritic cells express Tim-3, and its interaction with galectin-9 leads to inactivation of antigen-presenting cells. Furthermore, tumor galectin-9 interacts with dectin-1 on macrophages to promote tumor tolerance.

Thus, tumor galectin-9 plays an important role in controlling myeloid cell identity, T cell activation, and controlling effectors of antitumor immune responses.

 

 

 


Application of Galectin in Tumor Therapy


Galectins can act as soluble factors affecting various stages of the antitumor immune response (T cell migration/activation/effector function). Therefore, galectins are attractive targets for intervention in tumor immunotherapy.

 

However, available experimental and clinical evidence suggests that blockade of galectins as monotherapy may not confer any significant advantage in cancer treatment.

However, galectins are associated with patient sensitivity or resistance to chemotherapy, radiotherapy, immunotherapy, anti-angiogenic and targeted therapies, and it may be possible to combine galectin inhibition with existing therapeutic strategies It is the best way to achieve effective treatment.

 

Inhibition of galectins combined with chemotherapy affects antitumor immunity.

In colorectal-liver metastases, single-cell analysis defined two distinct tumor cell subpopulations that respond differently to chemotherapy: stem-like cells (tumor cells that primarily utilize the PD-1/PD- L1 pathway to control immunity ) and intestinal Cell-like cells ( use Tim-3/galectin-9 pathway to escape immunity ).

Paclitaxel-based chemotherapy can be improved with neutralizing anti-Tim-3 or anti-galectin-9 antibodies.

 

The combination of galectin-1 inhibition and chemotherapy is another promising strategy for the treatment of certain types of cancer.

In fact, a synergistic therapeutic effect has been reported for the treatment of glioblastoma by combined inhibition of galectin-1 and temozolomide.

This combination therapy switches macrophages to M1 polarization, reduces myeloid suppressor cells and regulatory T cells, and increases CD4+ and CD8+ T cell infiltration of tumors.

 

Inhibition of galectins may also be a good strategy in combination with radiotherapy. Studies have shown that radiotherapy can increase the secretion of galectin-1 at the tumor level.

High circulating levels of galectin-1 are directly associated with lymphopenia and radiation resistance in cancer patients

In ovarian, breast, and squamous cell carcinoma models, administration of Anginex, a 33 amino acid galectin-1 inhibitory peptide , in combination with suboptimal doses of radiation resulted in tumor regression.

 

Inhibiting galectins could also enhance other immunotherapies. Data from head and neck cancers suggest that galectin-1 inhibition enhances anti-PD-1 therapy, suggesting that the combination of galectin-1 inhibitors and anti-PD1/PDL1 immune checkpoints could be synergistic in cancer therapy.

Furthermore, the selective galectin-1 inhibitor OTX008 inhibited tumor growth in some preclinical studies. In 2012, a Phase I clinical trial ( NCT01724320 ) was announced to evaluate the effect of subcutaneous injection of OTX008 in the treatment of advanced solid tumors . So far, no results have been communicated.

 

In lung cancer, accumulation of Tim-3-expressing lymphoid cells and galectin-9-expressing monocyte myeloid-derived suppressor cells was positively associated with resistance to anti-PD1 immunotherapy. Therefore, anti-PD-1 drug resistance can be overcome by blocking the galectin-9/Tim-3 pathway in vitro.

The results support a phase I/II trial ( NCT02608268 ) that is evaluating the safety and efficacy of the anti-Tim-3 antibody MBG453 as a single agent and in combination with anti-PD-1 in patients with advanced malignancies.

 

Galectin-3 is a major determinant of cold tumors, and inhibition of galectin-3 may reverse this resistance.

Oral administration of a galectin-3 inhibitor ( GB1107 ) reduces growth and blocks metastasis in human and mouse lung adenocarcinomas in a syngeneic model .

In addition, GB1107 potentiated the effects of PD-L1 immune checkpoint inhibitors to increase the production of cytotoxic effector molecules.

In metastatic melanoma and head and neck cancer, a galectin-3 inhibitor ( GR-MD-02 ) improves anti-PD-1 therapy.

 

Taken together, the available information highlights the critical role played by galectins in resistance to anti-PD-1 therapy and supports the importance of galectin inhibition in combination with checkpoint inhibitors.

Therefore, several clinical trials are underway, treating patients with different tumor types with galectin-3 inhibitors and immunotherapy.

These clinical trials include non-small cell lung cancer, head and neck squamous cell carcinoma ( NCT02575404 ) and melanoma ( NCT02117362, NCT02575404 ).

 

 

 


Summary


Galectins play an important role in tumor immunity. Galectin-1, -3, -7, -8, and -9 are the main molecules for tumors to escape immune control. T

argeted inhibition of these galectins may play a role in combined radiotherapy, It plays an active anti-tumor role in chemotherapy, immunotherapy and targeted therapy.

This requires us to more accurately elucidate their precise mechanisms of action in vivo, develop more potent and selective inhibitors, and combine these molecules with other anticancer strategies in a rational manner.

 

 

 

 

 

 

 

 

 

 

 

references:

1. Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure. Cancers (Basel). 2021 Sep;13(18): 4529.

What is the role of Galectin in tumor immunity?

(source:internet, reference only)


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