Chapter 12: Tumor immunology and immunotherapy and inflammation (Book, main)

Question 1

I think a lot of these cards are already seen as ‘common knowledge’, but just in case: the following cards will be refresher.

Answer 1

Ok

Question 2

Immune cells arise from two types of progenitor cells. What two cells?

Answer 2

Myeloid and lymphoid progenitor cells.

Question 3

Name cells that respond early and non-specifically to infection and are thus part of the innate immune response.

Answer 3

Neutrophils, eosinophils, basophils, dendritic cells, natural killer cells and macrophages.

Question 4

Name cells that respond later during infection and are thus part of the adaptive immune response.

Answer 4

B cells and T cells (helpter T cells and cytotoxic T cells).

Question 5

How can the immune system play a dual role in cancer?

Answer 5

It as both anti-tumor as pro-tumor effects.

• Anti-tumor: immune cells can recognize and eliminate tumor cells.
• Pro-tumor: antigens of cancer cells that are shaped by the immune system could lead to evasion of the immune system and cancer promotion.

Question 6

What is the main function of B cells?

Answer 6

To synthesize and secrete antibodies (humoral immunity). Antibodies can recognize almost any antigen encountered by the immune system and can coordinate cell-mediated cell lysis.

Question 7

Antibody production may be triggered by protein, lipid, or polysacchardide antigens and requires B cell-T cell interaction. What is the result of this interaction?

Answer 7

B cell differentiation into memory B cells and plasma cells that produce IgG antibodies.

Question 8

How can a single clone of a specific B be grown experimentally in order to produce quantities of a specific monoclonal antibody?

Answer 8

By creating hybridoma, a hybrid cell formed by fusing a B cell with a B cell cancer cell (myeloma).

Question 9

T cells (CD4+ and CD8+ effector T cells) are responsible for cell-mediated immunity. What does this mean?

Answer 9

That they have membrane-bound T cell receptors that can recognize antigens that are presented to them via antigen-presenting cells (APC).

Question 10

What is the main target of T cells?

Answer 10

Virus-infected cells and tumor cells.

Question 11

What is the function of T regulatory cells?

Answer 11

They suppress the function of immune cells and are important regulators of the immune response.

Question 12

The immune system protects against cancer in three ways. Name these.

Answer 12

1. Protection from viral and bacterial infection that may be caustive agents of cancer.
2. It helps resolve inflammation, a promotor of cancer.
3. It can recognize and kill tumor cells.

Question 13

What is immunosurveillance?

Answer 13

The concept (hypothesized in mid-20th century) that the immune system recognizes cancer cells as foreign agents and eliminates them.

Question 14

The cancer immunity cycle has already been broadly discussed in the lecture. There will be a few cards about this topic in this deck.

Answer 14

Ok

Question 15

What are the 7 steps in an immune response against a tumor?

Answer 15

1. Release of cancer cell antigens during tumor cell death.
2. Cancer antigen presentation on APCs.
3. Priming and activation of T cells in lymph nodes
4. Transport to tumors via the bloodstream
5. Infiltration of T cells into tumors
6. Recognition of cancer cells
7. Tumor cell death

Question 16

How can antigens be distinguished from self antigens?

Answer 16

Tumors have tumor-specific antigens (molecules that are unique to cancer cells) or tumor-associated antigens (molecules that are differentially expressed in cancer and normal cells).

Question 17

Through what molecules on APCs are (tumor) antigens presented so that T cells can recognize the antigen and can get activated?

Answer 17

Major histocompatibility complex (MHC) molecules.

Question 18

What is T-cell priming?

Answer 18

The events initiating the process of quiescent naive T cells to activated effector T cells.

Question 19

What is one of the most important anti-tumor defenses of the body (that also has memory)?

Answer 19

The cytotoxic T-cell response.

Question 20

Describe T cell activation in short

Answer 20

APC presents its antigen through MHC to TCR of T cell. CD28 on T cells then binds with its ligand B7 on the APC. This initiates a full T cell response. (There’s also T cell differentiation after T cell activation).

Question 21

What molecules is a competitive inhibitor of B7 and competes with CD28 for binding?

Answer 21

CTLA-4, it binds more stronly than CD28 to B7. If CTLA-4 binds, it serves as a negative feedback signal and suppresses T cell function.

Question 22

Describe differences between MHC class I and class II molecules.

Answer 22

• Antigens bound by class I are recognized by CD8+ T cells. Antigens bound by class II are recognized by CD4+ T cells.
• MHC class I is involved in presentation of intracellular antigens, MHC class II is involved in presentation of extracellular antigens
• Complex of MHC I + intracellular antigen is transported to the cell surface for antigen presentation. MHC II-extracellular antigen complex are formed in lysosomes and then transported to the cell surface.

Question 23

Programmed death 1 protein (PD-1) and its ligands PD-L1 and PD-L2 are additional co-inhibitory molecules. PD-1 is expressed on T cells. On what cells are its ligands expressed?

Answer 23

PD-L2 is expressed on APCs. PD-L1 is expressed on many cell types, including tumor cells, after IFN-y production by effector T cells.

Question 24

What does interaction of PD-L1 on tumor cells and its receptor on activated effector T cells cause?

Answer 24

The recruitment of SHP-2 phosphatases and inactivation of the PI3K cascade, blocking the production and secretion of molecules required for a cytotoxic response.

Question 25

What are the three Es in immunoediting?

Answer 25

Elimination of cancer, equilibrium (the selection of less immunogenic tumors cells during an anti-tumor response) and escape whereby tumors evade the immune system.

Question 26

What supports the evidence that the immune system can affect the immunogenicity of a tumor?

Answer 26

Tumors formed in a deficient immune system are more immunogenic and are hence unedited, whereas tumors formed in immunocompetent hosts are termed edited.

Question 27

Name mechanisms for tumor evasion (don’t learn by heart).

Answer 27

Loss of tumor antigens, downregulation of antigen-presenting molecules and tumor resistance to cytotoxic pathway, including overexpression of immune checkpoint protein (e.g. PD-L1).

Question 28

What are immunosuppressive molecules that can be secreted by tumors?

Answer 28

TGF-b, IL-10, VEGF and indolamine-2,3-dioxygenase (IDO)

Question 29

Shortly describe the function of the immunosuppressive molcules TGF-b, IL-10, and IDO.

Answer 29

• TGF-b can bind to lymphocytes and alter their phenotype/cytokine secretion profile.
• IL-10 can prevent dendritic cell maturation and inhibits proliferation and cytokine production of CD4+ T cells.
• IDO is an enzyme that causes a reduction in the availability of amino acid tryptophan to T cells and inhibits their activation, prolfieration and survival.

Question 30

What do therapeutic antibodies mostly interfere with/cause?

Answer 30

They mostly interfere with signal transduction and/or engage with receptors on immune cells that leads to antibody-dependent cellular cytotoxicity or phagocytosis (Fc portion of antibody is important in this).

Question 31

Name types of therapeutic vaccines and shortly describe their function.

Answer 31

• Whole cell vaccines, all antigens that are expressed by a specific tumor are included in the vaccine (e.g. gene-modified tumor cells that express stimulatory molecules for T cells).
• Peptide-based vaccine, use of tumor-associated antigens or tumor-specific antigens to generate an immune response.
• Dendritic cell vaccine, reintroduction of isolated dendritic cells cultured and then loaded with specific antigens into the body.

Question 32

What kind of vaccine is Provenge and why?

Answer 32

Dendritic cell vaccine, since the vaccine contains a fusion protein that can mature and activate dendritic cells.

Question 33

In the setting of a cancer antigen that is being presented by this APC depicted in the picture. How can be prevented that CTLA-4 will bind to B7 and inhibit T cell activation?

Answer 33

Through the use of a human monoclonal antibody against CTLA-4.

Question 34

What is another checkpoint, except CTLA-4, that can be inhibited through the use of monoclonal antibodies?

Answer 34

PD-1 on T cell and PD-L1 on tumor cell. (Keep in mind that CTLA-4 prevent total activation of immature T cells while PD-1 blocks T cell activation after they turned into effector T cells).

Question 35

What does the concept of “hot” and “cold” immunogenic tumor environments say about the clinical benefit for patients that are treated with PD-1 and PD-L1 therapies?

Answer 35

Patients with PD-L1 negative tumors can also respond to anti-PD-1 or PD-L1 therapy. ((Probably because although these tumors were PD-L1 negative, these tumors are “hot” tumors. –> this is my own reasoning, since the book only tells that hot and cold environments correlate with clinical benefit of PD-1 and PD-L1 therapies but doesn’t tell in what way it correlates)).

Question 36

What is immunotherapy based on tumor-infiltrating lymphocytes (TILs)?

Answer 36

This therapy is based on adoptive cell transfer of naturally occuring T cells found in a tumor. These cells have been activated in response to tumor-associated antigens, but, in the body, they are restrained by immunosuppressive molcuels such as CTLA-4. TILs removed from the tumor are also removed from their immunosuppresive environment. This can be used in practice where tumor is cut into small fragments and is cultured to produce pure cultures of lymphocytes. After selecting for anti-tumor activity, they can be expanded ex vivo and transferred back to the patient.

Question 37

Adoptive cell transfer strategies (like TIL immunotherapy) can also involve genetically modifying T cells from the blood, so that they express TCRs that target specific tumor antigens. What T cells are created in this way?

Answer 37

Chimeric antigen receptor (CAR) T cells.