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Exercise and Clinical Immunology > Cancer - L10 > Flashcards

Cancer - L10 Flashcards

1
Q

What is the multiple hit model in cancer?

A

That cancer is caused by a combination of genes with mutations.

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2
Q

Explain how mutations can lead to autonomous growth.

A
  • Presence of growth factor that when binding to a tyrosine kinase domain results in ligand-dependent firing.
  • Mutation to receptor leading to ligand-independent firing.
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3
Q

Explain the process of metastasis.

A
  • Primary tumor formation
  • Localized invasion
  • Intravasation (entering of lymph or blood vessels from primary tumor)
  • Transport through circulation
  • Arrest in microvessels in various organs
  • Extravasation (leaving lymph or blood vessels to enter (new) tissue)
  • Formation of micrometastasis
  • Colonization - formation of macrometastasis
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4
Q

Name the hallmarks of cancer.

A
  • Sustaining proliferative signaling
  • Evading growth suppressors
  • Avoiding immune destruction
  • Enabling replicative immortality
  • Tumor-promoting inflammation
  • Activating invasion and metastasis
  • Genome instability and mutation
  • Resisting cell death
  • Deregulating cellular energetics
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5
Q

What are the 3 Es of immuno-editing? Explain them.

A
  • Elimination: i.e. cancer immunosurveillance where transformed cells with tumor antigens are recognized by the immune system, which activate the innate and adaptive immune system that eliminate the cancer cells.
  • Equilibrium: some cancer cells may survive the immune system, but are held in check by the immune system. Cancer cells may enter a dormant state, preventing the development of a full-grown cancer. The immune system keeps these cancer cells in check, maintaining a state of equilibrium.
  • Escape: the immune system fails to tackle the cancer (e.g. by immune evasoin of cancer cells) resulting in cancer progression and chronic inflammation. These cancer cells may employ various strategies to escape immune recognition.
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6
Q

How do tumors use/shape their microenvironment to escape the immune response?

A
  • Immunoselection of poorly immunogenic tumor cells.
  • Recruitment of immunosuppressive immune cells
  • Immunoevasion at tumor cell level
  • Soluble tumor-derived products that inhibit antitumor immunity
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7
Q

Tumor infiltrating lymphocytes (TILs) are lymphocytes that have invaded the tumor tissue. What do these cells predict?

A

Survival. Many TILs is associated with a increased survival compared to few TILs.

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8
Q

What is immunotherapy?

A

Therapy that works by boosting or modifying the body’s natural immune response to target and destroy cancer cells.

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9
Q

Name examples of cancer immunotherapies.

A
  • Immune checkpoint inhibitors(block specific protein on the surface of immune cells. They can inhibit the immune response and prevent it from attacking cancer cells. This help unleash the immune system to attack cancer cells more effectively)
  • Viro-immunotherapy
  • Adoptive cell transfer
  • Cytokine therapies
  • Cancer vaccines (designed to stimulate the immune system to recognize and attack cancer cells)
  • CAR-T cell therapy (genetically modifying patient’s T cells to express a receptor that targets a specific protein on the surface of cancer cells)
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10
Q

Describe in short how the immune system is activated as a result of tumor formation.

A

Resident dendritic cells near the tumor ‘sense’ the formation of the tumor. The dendritic cells (now APCs) migrate to the lymph node and activate T cells. The T cells then migrate to the tumor and kill tumor cells.

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11
Q

What is the Mellman cancer immunity cycle? Also explain the cycle.

A

A cycle that explains which series of events occur to initiate anti-cancer immune responses.
1. Release of cancer cell antigens
2. Cancer antigen presentation
3. Priming and activation of immune cells
4. Trafficking of T cells to tumor
5. Infiltration of T cells into tumor
6. Recognition of cancer cells by T cells
7. Killing of cancer cells

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12
Q
  • What is the problem with current immunotherapy trials for cancer?
  • What is the problem regarding evidence of benefits of exercise for cancer?
A
  • Not enough patients
  • Little evidence in humans
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13
Q

How does exercise mobilize the immune system? Explain which cells and molecules are involved in this response.

A

During exercise, there is an increase in catecholamine levels, which are thought to drive the mobilization of immune cells into the circulation. Subsequently, the concentration of circulating immune cells increase. The highest increase is seen for NK cells, but T and B cells also increase. It is believed that the myokines produced by skeletal muscle as a result of exercise are important for the redistribution of these immune cells after exercise.

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14
Q

What is the interferon response?

A

Virus infected cells produce interferon molecules (specifically IFN-α and IFN-β). The interferon reponse induces:
* resistance to viral replication in all cells
* increase in expression of ligands for receptors on NK cells
* activates NK cells to kill virus-infected cells

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15
Q

How does a NK cell kill a virus-infected cell?

A
  • Virus infection of cells trigeers the interferon response.
  • Type I interferon drives the proliferation of NK cells.
  • Type I interferon drives the differentiation of NK cells into cytotoxic effector cells.
  • Effector NK cells kill virus-infceted cells by inducing them to undergo apoptosis.
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16
Q

NK cell function is regulated by a delicate balance between activating and inhibitory receptors. Explain this.

A

NK cells need to distinguish cells that are healthy and cells that are not. In the case of healthy cells NK cells need to be inhibited, whereas in the case of tumor cells, NK cells need to be activated.

  • Tolerance of own healthy cells by NK cells is accomplished by the fact that healthy cells carry MHC molecules on their surface that can interact with inhibitory receptors on the surface of NK cells. Healthy cells also carry an activating ligand on their surface that interact with an activating receptor on the NK cell surface. However, the inhibitory signal here is much stronger.

In the case of tumor cells, there are two ways a NK cell can by activated:

  • Tumor cells often do not express MHC molecules anymore. Therefore, the inhibitory interaction between an MHC molecule and the inhibitory receptor on the NK cell cannot occur anymore. Therefore, the NK cell is activated upon interaction with a tumor cell that misses an MHC molecule.
  • Some tumor cells do express MHC molecules. In this case 2/5 of the interaction is inhibitory, but 3/5 of the interaction is activating. As a result, there is upregulation of stress-induced ligands that promote the killing of the tumor cell.
17
Q

What associated is there between exercise and NK cells regarding tumors?

A

Exercise increases intratumoral NK cell infiltration

18
Q

So exercise is associated with increased intratumoral NK cell infiltration.
What happens to NK cell infiltration when propranolol (blocks (nor)epinephrine) is administered?

A

Normally, exercising would result in an increased mobilization of NK cells. By adminstering propranolol, the mobilization of NK cells is blocked. Therefore, mobilization of NK cells is (nor)epinephrine dependent. The same was observed for tumor volume, where propranolol blunted the effect of running on tumor volume.

19
Q

Describe the exercise-induced antitumor NK response.

A
  • Exercise results in an increase in epinephrine.
  • Epinephrine results in the mobilization of NK cells.
  • Myokines IL-6, IL-7, IL-15 produced from skeletal muscle in response to exercise stimulate the maturation and redistribution of NK cells into the tumor.
20
Q

What are symptoms of (cancer) cachexia?

A
  • Unintentional weight loss
  • Anorexia/loss of appetite
  • Skeletal muscle wasting
  • Lowered QoL
21
Q

Name the top three cancers with the highest prevalence for cachexia.

A
  • Pancreatic cancer
  • Gastro-oesophageal cancer
  • Head and neck cancer
22
Q

What process is stimulated by the presence of a tumor and could expain loss of muscle mass in cachexia patients?

A

Ubiquitin mediated muscle protein degradation that is activated through a variety of pathways/triggers.

23
Q

Tumor formation results in:

  • alterations in protein and amino acid metabolism
  • increased inflammatory mediators
  • decreased regeneration

How do the alteration in protein and amino acid metabolism and the increase in inflammatory mediators result in loss of skeletal muscle mass and function?

A
  • alterations in protein and amino acid metabolism -> increased proteolysis, decreased protein synthesis, decreased amino acid transport, and increased BCAA oxidation.
  • increased inflammatory mediators -> increased apoptosis.
24
Q

How does cancer benefit from the increased protein degradation?

A
  • Protein degradation results in increased (serum) levels of glutamine and alanine originating from muscle proteins and increased glycerol and NEFA originating from adipose tissue.
  • Alanine and glycerol can be converted to glucose in the liver.
  • Glucose, glutamine, and NEFA are used for metabolism of the tumor.
  • The tumor also generates lactate, which can be converted to glucose by the liver, which the tumor can then use ‘again’.
25
Q

Name processes that occur in the following organs that can lead to cancer cachexia (i.e. skeletal muscle wasting):
* Brain
* Brown adipose tissue
* White adipose tissue
* Heart
* Gut
* Liver

A
  • Brain: anorexia -> altered patterns of hypothalamic mediators, loss of apetite, hyposmia, hypogeusia.
  • Brown adipose tissue: thermogenesis -> energetic inefficiency
  • White adipose tissue: wasting -> increased lypolysis, release of fatty acids and inflammatory mediators.
  • Heart: cardiac dysfunction -> atrophy, decreased innervation, increased energy consumption, release of inflammatory mediators.
  • Gut: malabsorption -> gut-barrier dysfunction, altered ghrelin production, release of inflammatory mediators.
  • Liver: acute-phase response -. release of acute-phase proteins, reduced albumin synthesis, release of inflammatory mediators.
26
Q

Name five pathophysiological processes that are a result of cancer and low skeletal muscle mass/inactivity that result in poorer clinical outcomes.

A
  • Systemic inflammation and altered myokine production
  • Mitochondrial dysfunction
  • Altered insulin-dependent glucose handling
  • Altered protein status
  • Altered pharmacokinetics

Exercise and Clinical Immunology (16 decks)

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