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Clear and complete summary of Tumor Immunology (TI)
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Clear and complete summary of Tumor Immunology/Clear and complete summary of Tumor Immunology (TI)
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SummaryHow tumor glycans contribute to immune evasion in cancer
N-linked = Glycan linked to Asn (asparagin ofzo). O-linked = glycan linked to Ser or Thr. There are hybrid
and complex glycans. Glycosylation by glycosyltransferases occurs in the ER and in the Golgi apparatus.
Altered glycosylation altered cell signalling pathways cancer. Glycoproteins are common used
biomarkers for cancer diagnosis and prognosis. Glycosylation can cause avoiding of immune destruction.
Important tumor-associated glycans:
1. Upregulation of sialic acids
2. Appearance of truncated (shorter) O-glycans (MGL ligands)
Lectins are glycan receptors on immune cells (e.g. APCs). There are C-type (CLR = C-type Lectin
Receptor) and L-type Lectins (SigLecs). Various ligands for the C-type. Only sialic acid is a ligand for L-
type lectins (Siglec).
These lectins (glycan receptors) are inhibitory; they can dampen the immune response with ITIM motifs.
Sialic acid on glycans on the tumor cell can induce macrophage modulation these macrophages will
produce TGF-b and IL-10 dampened immune response.
Hypersialyation (many sialic acids) immune evasion of tumor cells because sialic acid induces Treg
differentiation by DCs (Th1 Treg shift).
Solution: inhibit/KO the sialic acid transporter that pumps SA into the golgi less SA in golgi less SA
can be added to the cell surface by glycosyltransferases.
Summary
Lectins are inhibitory glycan receptors
Siglec = L-Type lectin sialic acid is ligand
Sialic acid induces immunotolerance (more Tregs, less NK cell response) immune escape
Glycosyltransferases perform glycosylation in the golgi apparatus
,Glycosylation changes in cancer
In melanoma (B16, right), high sialic acid leads to tumor growth,
because sialic acid induces immune tolerance (Tregs).
In colorectal cancer (MC38, left), no sialic acid leads to cancer.
These colorectal tumors (without Sialic acid) recruit less T cells and
even secrete factors that induce apoptosis of T cells (cold tumor).
C-type Lectin Receptor (CLR). C stands for calcium Ca dependent recognition of specific glycan
structures. Also important in cell-cell adhesion. Selectins (C-type lectin) recognize glycans of bacteria
and viruses. Selectins degrade them alter cytokine expression determines the T cell response.
5 potential O-glycosylation sites. A lot of
glycans can be attached. In tumors they
become really short (truncated). These short
glycans are ligands for MGL (Macrophage
Galactose-type Lectin) receptor on APCs in
skin and gut.
Tn- and Sialyl-Tn Ags are ligands for MGL.
In Colon carcinoma, MGL detects glycan changes on tumor-derived MUC1. MGL-MUC1 binding scores
(brown is very strong). Stage I & II still in the colon. III is metastasis to LN. IV is metastasis to liver.
High binding of MGL to tumors means poor survival.
MGL triggering on DC leads to high IL-10 production and thus to anergic/regulatory T cells. Solution:
Anti-MGL less IL-10 produced.
Summary
Tn-antigen / Sialic-Tn-antigen / Mucins on cell surface
dysregulation of immunity, escape from immune surveillance, progression and metastasis
Tumors/Pathogens use glycans to escape the immune response
Melanoma high sialic acid leads to cancer due to immune tolerance
CRC no sialic acid leads to T cell apoptosis and thus to cancer.
Selectins optimize/fine-tune the immune response
High MGL-MUC1 binding in CRC = poor survival
, Transcriptional immune profiles for cancer prognosis and therapy selection !’s checken in PP
Immuno-Editing = Elimination (immunosurveillance) equilibrium escape. Tumor cells that are
weakly immunogenic are able to escape. Tumor cells that are strongly immunogenic are destructed.
Immune profiling (e.g. by a biopsy) can identify biomarkers
prognostic (predict survival irrespective of treatment)
o Patients WITH 12-chemokine (signature) lived longer
predictive (predict clinical outcome/survival on a specific treatment) biomarkers
o Randomized clinical trial necessary
A liquid biopsy is better than a traditional biopsy because it is taken out of the blood (more cells to
investigate), it is less painful and easier to obtain (more often).
Endogenous IFN-beta signalling is required for intratumoral
accumulation & migration of (cross-priming) CD8α+ DCs.
DAMPs
and PAMPs trigger IFN-I gene transcription via the (Stimulator
of Interferon genes) (STING pathway. dsDNA is sensed in the
cytoplasm. Check IFN-induction @next page.
When a patient gets chemotherapy (e.g. doxorubicin), the tumor cell expresses Calreticulin (CRT) on the
outside (normally on the inside of cell) “come eat me” sign to immune cells. MHGB1 (a protein with a
high mobility) is then released by the tumor cell and binds to a DC DC activation T cell activation
tumor cell apoptosis.
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