Chapter 12 and 13: Immunology, immunotherapy and inflammation (Secondary details)

Question 1

What two cells are the main players in cancer immunology?

Answer 1

T cells and dendritic cells

Question 2

Just a quick refresher, fill in: -CD8+ T cells recognize antigens presented through *MHC class I or MHC class II*. -CD4 T cells recognize antigens presented through * MHC class I or MHC class II*.

Answer 2

-CD8+ T cells recognize antigens presented through *MHC class I* -CD4+ T cells recognize antigens presented through * MHC class II*

Question 3

How do CD8+ T cells become active?

Answer 3

CD8+ T cells express a T cell receptor that can very specificly recognize a peptide derived from a protein/antigen from the target cell in the context of MHC class I molecules. (This peptide that is recognized by the CD8+ T cell can be “direcly” presented by a tumor cell (through MHC molecule) or “indirecly” by a dendritic cell that presents a tumour antigen to the T cell).

Question 4

What signal is really important in T cell activation?

Answer 4

Signal 2, without it T cells cannot respond to signal 1 and become anergic/tolerized. This is also logical because if only signal 1 is needed for T cell activation, T cells can respond to any antigen.

Question 5

What are scavenger receptors?

Answer 5

Receptors that can bind tissue residues for engulfment.

Question 6

What helps dendritic cells to become active?

Answer 6

Cytokines (coming from tissue damage or inflammatory responses), bacterial or viral components or TLR-L.

Question 7

I hope/don’t think we need to learn this, but for overview purposes match Toll-Like Receptor (TLR) types with specific pathogens.

• Toll-Like Receptors: TLR7 and TLR8, TKR5, TLR9, TLR4, TLR3, TLR6 en TLR4, TLR2 en TLR1.
• Pathogens: viral ssRNA, bacteria (flagellin), yeast, viral dsRNA, bacteria (LPS)

Answer 7

First it is helpful to know that TLR7 and 8, TLR9 and TLR3 are in endosomes. TLR1-6 (except TLR3) are on the cell-surface of APCs.

• TLR7 and 8 bind viral ssRNA
• TLR9 binds bacterial CpG DNA -TLR3 binds viral dsRNA
• TLR 1 and 2 bind bacteria and yeast
• TLR 6 and 2 bind bacteria and yeast
• TLR4 binds bacteria (LPS) TLR5 binds bacteria (flagellin)

Question 8

An antiviral immune response can be created when certain TLRs are activated. What molecules can be expressed for this antiviral immune response? This is also the case for T cell stimulation and inflammation. What are molecules needed to be expressed for this response?

Answer 8

-Antiviral immune response -> IFN-a or IFN-b -T cell stimulation -> expression of co-stimulatory molecules (CD40, CD80, CD86) -Inflammation -> IL-1b, IL-6, IL-12, IL-8, TNF-a

Question 9

What do approved indications for immunotherapy mostly respond well to?

Answer 9

To either a tumor with viral etiology or tumors with high DNA mutation load

Question 10

Provenge was approved for use as a treatment. Was it really a good treatment?

Answer 10

No, clinical trials showed little improvement of survival rate of patients with prostate cancer. The vaccine resulted in 4 months extra to live (approximately). The vaccine was actually only approved due to prostate cancer patients wanting to have another option. This vaccine turned out to actually have very little improvement in survival rate.

Question 11

What are examples of active immunotherapy and what are examples of passive immunotherapy?

Answer 11

-Active immunotherapy: generating T cells in vivo by getting a vaccine or the example with the oncolytic virus -Passive immunotherapy: cytokines, antibodies, T cells.

Question 12

What was the clinical response to the vaccination with in vitro primed/expanded T cells against melanomas?

Answer 12

The clinical response was measured in up to 70% of treated patients

Question 13

What’s the difference between first and third generation CAR T cells?

Answer 13

First generation T cells only contain the TCR and the anti-CD19 CAR. Third generation T cells also contain co-stimulatory signals like CD28 or 4-1BB that optimize T cell activation and survival.

Question 14

What is a respiratory burst?

Answer 14

Respiratory burst (or oxidative burst) is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types (like immune cells)..

Question 15

How can tumor cells escape the immune system?

Answer 15

Downregulation of MHC class molecules, release of immune suppressive factors or upregulation of Treg cells.

Question 16

What are factors that induce dendritic cell maturation?

Answer 16

GM-CSF, IL-12, IL-4

Question 17

What are factors that suppress dendritic cell maturation?

Answer 17

IL-10, VEGF, IL-6, PGE2, M-CSF, IDO

Question 18

Just have a look at this picture. You should get the difference.

Answer 18

Ok

Question 19

When you look to a tumor with the help of immunohistochemisty, what can you see most often next to a PDL1 expressing tumor?

Answer 19

Infiltrations of T cells (this tells you that T cells probably caused the PDL1 expression).

Question 20

Iets over bcr?

Answer 20

ok

Question 21

What has been termed as the immunoscore?

Answer 21

The characterization of T cell infiltration into the tumor as a biomarker or prognostic indicator (e.g. melanoma patients with high levels of CD8+ cell infiltration survive longer than those with tumors containing low numbers of these cells (also patients with high Treg number have a bad prognosis).

Question 22

What are antibody-drug conjugates (ADCs)?

Answer 22

Antibodies linked to chemotherapeutic agents form ADCs, they can deliver drugs specifically to the tumor.

Question 23

What is the difference between a therapeutic vaccine and a prophylactic vaccine?

Answer 23

-Therapeutic vaccine are designed to stimulate the immune system in order to cause tumor regression in a patient with cancer. -Prophylactic vaccines (vaccines with shared tumor antigens) are designed for cancer prevention to prepare the immune system prior to getting cancer.

Question 24

What is less likely to result in an autoimmune reaction, whole cell vaccination or peptide-based vaccination?

Answer 24

Peptide-based vaccination with tumor-specific antigens.

Question 25

Is the safety profile higher for drugs that inhibit early (like CTLA-4) or late checkpoints (PD-1, PD-L1)?

Answer 25

For late checkpoints like PD-1 and PD-L1

Question 26

Why are females less susceptible to liver cancer?

Answer 26

IL-6 is produced by liver macrophages which seems to have an important role in hepatocarcinogenesis. IL-6 is downregulated in response to estrogen, which is why females are less susceptible.

Question 27

Nf-kB is a dimeric transcription factor made up of hetero- or homodimers of protein members in the NF-kB family. This family is placed into two groups. The first group consists of p65, Rel B and c-Rel. The second group of NF-kB 1 (p50) and NF-kB2 (p52). What is the difference between these two groups?

Answer 27

The first group of proteins are synthesized as mature products, whereas the second group of proteins must be proteolytically processed to produce mature p50 and p52 proteins.

Question 28

What is the most important cellular effects of NF-kB activation?

Answer 28

Inhibition of apoptosis via the induction of anti-apoptotic gene expression (e.g. Bcl-X1, c-IAP, cFLIP). It can also activate cyclin D1 gene and thus plays a role in regulation of the cell cycle. It can also induce transcription of MDM2 and inhibit p53.

Question 29

The world’s first cervical cancer vaccine contains the major capsid protein L1 from four types of HPV (6, 11, 16 and 18). Do they all prevent cervical cancer?

Answer 29

The vaccine can prevent cervical cancer caused by HPV16 and HPV18. And can prevent precancerous lesions and warts caused by HPV6, -11, and -18.

Question 30

Many research groups are focusing on strategies to inhibit NF-kB activation. What is their focus mostly on?

Answer 30

Selective inhibition of IKK activity to inhibit NF-kB activation.