Wk 7 Cancer and Immunology

Question 1

What 3 processes result in immunoediting?

Answer 1

1. Elimination = Immunosurveillance: elimination of tumors by the immune system. When not successful, progression occurs.
2. Equilibrium = Darwinian selection of tumor variants
3. Escape = Ultimate consequence of “equilibrium” phase and appearance of clinically
   apparent tumors

Question 2

What happens in the elimination process?

Answer 2

=subclinical
1. Tumors grow invasively, require blood supply -> produce stromogenic and angiogenic proteins
2. inflammation induced. Innate cells recruited (NKT, NK, gamma….T cells, macrophages, dendritic cells, CD8+ T cell most Important!)
3. IFN gamma produced, causing some tumor cell death, recruitment and activation of NK cells and macrophages
4. Tumor cell debris taken up by DC’s – home to lymph nodes
5. Initiation of adaptive immune response

Question 3

What kids of immune evasion occur?

Answer 3

1. *Loss of MHC or antigen expression
2. *T cell expression of negative costimulatory molecules: CTLA-4, PD-1
   *Tregs: IL-10, TGF-beta
   *Myeloid-derived suppressor cells (MDSC)
   *Loss of inflammatory (M1) macrophages
   *Clinically observable malignant disease occurs
   Tumors can be hypoxic

Question 4

Why do tumors escape control by the immune system?

Answer 4

1. Loss of tumor antigens or MHC
2. Active immunosuppression: Tregs
3. Non-protective immune responses

Question 5

What viruses are good at downregulating MHC class I?

Answer 5

Herpesviruses

Question 6

What happens to tumor cells when there is loss of expression of HLA class I proteins?

Answer 6

They are susceptible to NK cells, but NKs are often insufficient on their own to suppress tumor growth

Question 7

What IS cells are found in many human cancers?

Answer 7

Tregs
*Associated with decreased survival
*Induces cycle of immune suppression
*Directly suppress activated T cells
*Convert activated APCs into suppressive APCs
*IL-10, TGF beta

Question 8

Diagram of tumors and the non-protective immune response they induce

Answer 8

Question 9

What are 5 things we can do to promote anti-tumor therapy?

Answer 9

1. Cancer vaccines
2. High Dose IL-2
3. Transfer of tumor-specific T cells
   - Adoptive cell therapy (ACT)
   - Chimeric antigen receptor (CAR) T cells
4. Checkpoint blockade (anti-CTLA-4, anti-PD-1)
5. Monoclonal antibodies

Question 10

What is adoptice cellular therapy (ACT)?

Answer 10

• In vitro expansion of tumor antigen specific CTL
• Development of T cell lines that are tumor-specific
• Cloning of high affinity TCRs, gene transfer into effector CTL
• Injection back into patient
• Very personalized, very expensive, high expertise required

Question 11

What are CAR T cells?

Answer 11

=chimeric antigen receptor T cells
-can be used to target tumors like B cell lymphomas expressing CD19 (overexpressed in certain B cell lymphomas)

70-90% complete response rate for B-ALL

Question 12

What does it mean to block checkpoints?

Answer 12

Remove (block) pathways that inhibit tumor immunity. PD-1 and CTLA-4 inhibit TCR and CD28 signaling
1. anti-CTLA4 (ipilimumab)
2. anti-PD-1 (nivolumab, pembrolizumab)
3. anti-PDL1 (Atezolizumab, Avelumab, Durvalumab)