Cancer mechanisms and immune defense MED-MIN4 (MEDMIN04)
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Radboud Universiteit Nijmegen (RU)
All the notes from the course MIN04 written in English. Overall, the course MIN04 provides a comprehensive overview of the interdisciplinary field of cancer research, encompassing molecular biology, immunology, cancer diagnostics, treatment, cell culture, cancer genomics, computational modeling, ra...
Cancer mechanisms and immune defense MED-MIN4 (MEDMIN04)
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Learning goals: you understand the molecular and clinical principles of cancer research, and can exploit these to
design next-generation (immune)therapies against cancer.
Objectives: Explain/discuss the broad spectrum of cancer research, and selected cancer and immunology topics
in more depth. Design, preform and present biomedical research. Translate fundamental biomedical knowledge
into personalized therapeutic applications.
MIN04 introduction 9-10:30h 06/09/2021:
Cancer is a group of different diseases, all marked by uncontrolled growth of cells that can spread or invade other
parts of the body.
Most prevalent cancer sites for male: prostate (29%) and lung cancer (14%)
Most prevalent cancer sites for female: breast (30%) and lung cancer (14%)
Colon and rectum cancer is also predominant in males and females.
The development of cancer includes a multistep process.
7 mutations needed for a healthy cell to become malignant
The 8 hallmarks of cancer:
1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Activating invasion and metastasis
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Resisting cell death
7. Reprogramming energy metabolism
8. Immune evasion
Tumor immunology research: the ambition to understand the body’s own immune system to develop curative
therapies for cancer patients.
DC-based vaccines using ex vivo loaded DCs to induce immunity.
1. Collect dendritic cells of patient by isolating them from blood
2. Mature DC’s using tumor antigens/fragments
3. Vaccinate patient with mature DC’s
,4. DC’s will activate T cells, which results in a specific immune response
5. Mature DC’s migrate easier; CD8 cytotoxic T cells lyse the tumour cells by creating toxins, and CD4 T cells are
important in providing help.
Need immune balance:
Immunity (tumor eradication) ------- interaction between DC and T cell ------- Tolerance (tumor growth)
Detection and interpretation of genomic abnormalities in cancer:
- Point mutations
- Copy number variations
- Aneuploidies (the presence of an abnormal number of chromosomes in a cell, which originates during cell
division when the chromosomes do not separate properly between the two cells)
Technologies:
‘classical’ karyotyping, next generation sequencing, copy number profiling.
Molecular mechanisms:
Tumor gene mutation burden (TMB) is the approximate amount of gene mutation that occurs in the genome of
a cancer cell. The immune system can identify cancer cells and activate an immune response by detecting these
mutations. Cancers with low mutation burden (TMB-low) have fewer mutations, decreasing the chance that one
will activate the immune system. Immune cells may not identify cancer cells for many reasons, including lack of
appropriate markers on the tumor cell surface. Cancers with TMB-high have more mutations, increasing the
chance that at least one will activate an immune response. Immune cells can potentially identify cancer cells
from specific markers that may be present on the cell surface due to cancer-related mutations. TMB can be
measured using detailed molecular testing of tumor biopsy tissue (or tumor genetic material in the blood).
Tumor heterogeneity and clonal evolution. The clonal evolution model was first proposed in 1976 by Peter
Nowell. In this model, tumours arise from a single mutated cell, accumulating additional mutations as it
progresses. These changes give rise to additional subpopulations, and each of these subpopulations has the
ability to divide and mutate further.
Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome,
from one parent and no copies from the other parent. UPD can occur as a random event during the formation of
egg or sperm cells or may happen in early fetal development.
, Tumors can reprogram their energy metabolism
Tumor cells can inhibit immune cells, releasing molecules etc. they can hide from the immune system and inhibit
it. Immune evasion
MIN04 cancer treatments 10:30-11:30h 06/09/2021:
(systemic) cancer treatment for melanoma
Skin cancer is the most common form of cancer in the Netherlands (52%). The most common types of skin cancer
are basal cell carcinoma (BCC), planocellular carcinoma (PCC) and melanoma (which is the most invasive and
deadly).
Melanoma can extend to the blood and lymph vessels
How to separate a normal mole from a melanoma. Look at ABCD signs: asymmetry, border ((ir)regular), color
and diameter (larger than a pencil’s eraser).
Local treatments: surgery (1800s) and radiation therapy (early 1900s).
Systemic treatments: chemotherapy (early 1940s), targeted therapy (2000s) and immunotherapy (2010s).
Case: excision by dermatologist, examination by pathologist (melanoma, Breslow-depth 1,2 mm), might spread
to the lymph node; sentinel node procedure = negative, no further treatment. Sentinel node is the first lymph
node into which the lymphatic vessels open, from the area where the melanoma was located.
Chemotherapy
In common: damage to rapidly dividing cells. Different types of chemo and different specific side effects.
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