Glycosylation Changes in Cancer

• Glycan: ?

• Glycosylation: ?

• Glycan: A chain or structure made of sugar molecules.

• Glycosylation: The process of adding glycans to proteins or lipids.

Checkpoints in anti-tumour immunity

PD1

CTLA

KIR

SIRP

• PD-1 on T cells —- PD-L1 or PD-L2 on tumour cells = inhibit T-cell activity.

• CTLA-4 on T cells - CD28 (for B7 molecules) on antigen-presenting cells= reducing T-cell activation.

• KIRs on NK cells —- MHC class I molecules = inhibit NK-cell killing.

• SIRPα on macrophages —- CD47 on tumour cells = inhibits phagocytosis.

What is the glycocalyx?

A carbohydrate-rich layer covering the cell surface, formed by glycans attached to proteins and lipids.

How does cancer cells hijack glycosylation by post translational modification to suppress immunity

Altered tumour glycans can change immune recognition and engage inhibitory pathways that suppress anti-tumour immune responses.

What are the writers, erasers and readers of glycans?

1. Writers — glycosyltransferases

These enzymes add sugar molecules to a growing glycan structure.

2. Erasers — glycosidases

These enzymes remove sugars from glycans.

3. Readers — lectins and antibodies

These molecules recognise and bind particular glycan structures.

Where does protein glycosylation occur

ER and Golgi

What is the difference between N-linked and O-linked glycosylation?

N-linked glycans attach to asparagine; O-linked glycans commonly attach to serine or threonine.

Function of glycans

Which factors can alter a cell's glycosylation pattern?

•Age

•Infection

•Oncogenesis

•Differentiation

•Species & pathogens

When can glycosylation changes occur during tumorigenesis?

Early in tumour development, including during the transition from normal tissue to benign or premalignant lesions.

What are the Four important tumour-associated glycan changes and why only these 4 are seen commonly in cancer

1. Increased sialylation: Increased expression of sialic acids on glycans.

2. Truncated O-glycans: Incomplete or shortened O-linked glycan structures.

3. Increased fucosylation: Increased expression of fucose-containing structures.

4. Increased branching: More branched glycan structures, particularly among N-linked glycans.

Tumour evolution can select cells whose glycan changes provide a survival or growth advantage.

Name a few used biomarkers for cancer diagnosis and prognosis are glycoproteins

Glycans contribute to tumour progression. Name 3

• Receptor signalling and tumour-cell growth.

• Cell–cell adhesion.

• Interactions with the extracellular matrix.

• Interactions with immune cells.

• Tumour-cell migration and invasion.

• Metastasis and entry into or exit from blood vessels.

How are glycans detected by the immune system?

Through glycan-binding receptors/ lectins, that bind specific carbohydrate structures.

Why are lectins important in tumour immunology?

They allow immune cells to recognise glycans on tumour cells and can influence antigen uptake, immune activation and immunosuppression.

What are the three main families of immune-related lectins

C-type lectin receptors, Siglecs and galectins.

Where are sialic acids commonly located on glycans?

At the terminal signalling termination of glycosylation

How can increased tumour sialylation promote immune evasion?

Siglecs are receptors that bind sialic-acid-containing glycans.

Many Siglecs contain intracellular inhibitory signalling motifs, including ITIMs, which can reduce immune-cell activation.

• Tumour cells increase sialylation.

• Their sialylated glycans engage inhibitory Siglecs on immune cells.

• Inhibitory signalling reduces the immune response.

• Tumour cells become less susceptible to immune attack.

Roles of sialic acids in immunity

What are the main functions of C-type lectin receptors? How does tumour cell use it?

Carbohydrate recognition, cell adhesion, pathogen recognition, antigen uptake and modulation of immune responses.

Tumour-associated glycans can interact with CLRs and influence how dendritic cells and macrophages respond to tumour cells.

What are galectins and their functions

Carbohydrate-binding proteins

Function:

• Immune-cell activation and survival.

• Cell adhesion and cell–cell interactions.

• Cytokine responses.

• Communication between immune cells and the tumour microenvironment.

“Foreign” glycans can elicit a glycan-specific antibody response. Give an example

Neu5Gc in red meat

Are glycans immunogenic?

Glycan immunogenicity depends on factors such as:

• Whether the glycan is recognised as foreign or abnormal.

• How it is presented to the immune system.

• The availability of appropriate immune-cell activation signals.

• The immune tolerance mechanisms acting against self-like structures.

Why can hypersialylation promote immune evasion?

Hypersialylation means an increased level of sialic-acid-containing glycans on the cell surface.

• Cancer cells increase surface sialylation.

• Sialylated glycans bind inhibitory Siglecs.

• Inhibitory signalling increases.

• Immune-cell activation and anti-tumour activity decrease.

What is the effect of removing tumour sialyation

It changes the tumour immune environment towards improved anti-tumour control and reduced tumour burden.

High levels of sialic acids can dampen anti-tumor immunity, Explain

•Instruction of Tregs (melanoma)

•Inhibition of NK cell cytotoxicity

•Induction of tumor-associated, anti-inflammatory macrophages

Possible interventions to exploit glycans to treat cancer?

•Glycosidase targeting to the TME

•CAR-T cells specific for tumor-associated glycan structures

•Blocking antibodies to immune cell-expressed lectins