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FPP: pre-midterm > Tumor Immunity > Flashcards

Tumor Immunity Flashcards

1
Q

Describe the adaptive immune responses that can eliminate tumor cells

A
  • Helper Th1 CD4 T cells -> IL2, IFN gamma
  • Cytotoxic CD8 T cells -> granzyme and perforin
  • B cells -> soluble anti-tumor IgG, IgM, and complement mediated killing
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2
Q

What four antigen types will elicit a T cell response to cancer?

A
  1. Mutated self protein
  2. Products of oncogenes or mutated tumor suppressor genes
  3. Overexpressed or aberrantly expressed self protein
  4. Oncogenic virus
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3
Q

What four signals are required to produce activated effective anti-tumor CD8 CTLs?

A
  1. engagement of TCR with MHC I presented tumor peptide on APC
  2. engagement of co-stimulatory ligands CD80/86 (APC) with activating receptors CD28 (T cell)
  3. effector/memory cytokines (IL2, IL7, IL12, IL15, IFNa/b/gamma) provided by Th1, DC, and NK cells
  4. up-regulation of chemokine receptors required for T cell trafficking
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4
Q

What interaction is no longer necessary for activated/expanded CD8 CTLs?

A

They can directly see MHC I/peptide on tumor cells and NO LONGER require the presence of co-stimulatory proteins

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5
Q

What are the components of the innate immune response against tumors?

A
  • gamma delta T cells
  • NK cells
  • dendritic cells
  • macrophages
  • granulocytes (neutrophils)
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6
Q

How do gamma delta T cells respond to a tumor?

A
  • recognize phosphoantigens on tumor cells (express gamma delta TCR not the classical alpha beta)
  • cytolytic response
  • produce IFN alpha and IFN gamma
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7
Q

How do NK cells respond to a tumor?

A
  • produce IFN gamma
  • tumor cytolytic (liberate tumor antigens to DCs in order to induce DC activation/maturation)
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8
Q

How do DCs respond to a tumor?

A
  • secrete IL12 and type 1 IFNs
  • cross-present tumor antigen to CD8 T cells

**immature DCs are tolerogenic

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9
Q

How do macrophages respond to a tumor?

A
  • release proinflammatory tumoricidal mediators (ROS)
  • M1= high IL12 low IL10 (anti-tumor)
  • M2= low IL12 high IL10 (protumorigenic)
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10
Q

How do granulocytes (neutrophils) respond to a tumor?

A

Can be myeloid (BM) suppressors

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11
Q

What are IFN gamma’s anti-tumor actions?

A

**Type II interferon produced by activated NK and T cells

  • stimulates the immune system
  • activates macrophages (M1s)
  • induces MHC class II
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12
Q

What are IFN alpha/beta’s anti-tumor actions?

A

**Type I interferons

  • influence activation of innage (APCs) and adaptive immunity
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13
Q

What are IL12’s anti-tumor actions?

A
  • stimulates production of IFN gamma and TNF from T cells
  • enhances cytotoxicity
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14
Q

What are TNF’s anti-tumor actions?

A

**Tumor necrosis factor alpha

  • associated with acute phase inflammation
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15
Q

What is NKG2D?

A

An immune stimulatory receptor; the ligand is overexpressed by infected, transformed, senescent and stressed cells

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16
Q

What is TRAIL?

A

A death receptor ligand expressed on activated T cells

17
Q

What is perforin?

A

A cytolytic mediator produced by cytotoxic T cells

18
Q

What cytokines/factors of the innate immune system lead to tumor elimination?

A

IFN a/b/gamma, IL12, TNF, NKG2D, TRAIL, and perforin

19
Q

What immune suppressive cell types provide a barrier to cancer immunity?

A
  • tumor cells
  • T reg cells (produce TGF beta and IL10)
  • Th2 CD4 T cells (produce immune suppressive cytokines; IL4, IL6, IL10, IL13, and CSF1)
  • immature DCs (tolerogenic)
  • myeloid (BM) suppressor cells
  • M2 macrophages
20
Q

What function of prostaglandin E2 is inhibitory to the immune system?

A

Promotes T regs

21
Q

What is the main barrier to cancer immunity?

A

Cancers employ a variety of immune inhibitory mechanisms

**Bottom line; T cells are suppressed so they can’t get rid of the tumor…. a main breakthrough in cancer therapy was reactivation of anti-tumor T cells (allows return to equillibrium)

22
Q

What are the two main goals of cancer immunotherapy?

A
  1. Use various mechanisms to ramp up T cell activation
  2. Use antibodies that target tumor antigens resulting in tumor cell death (e.g. EGFR)
23
Q

What are the methods of “ramping up the T cells”?

A
  1. Block T cell inhibitory (checkpoint) receptors using antibodies
  2. Adoptive transfer of tumor-specific T cells
  3. Genetically manipulate T cells for adoptive cell transfer (chimeric antigen receptors or CAR T cells)
  4. Allogeneic T cells for anti-leukemia effect
  5. Bispecific antibodies (direst T cells to target molecules)
  6. Agonist Abs to co-stimulatory TCRs (CD40, CD137, ICOS, CD28, OX40)
  7. Peptide, DC, and DNA vaccines
  8. Immune stimulatory agents
24
Q

What are immune checkpoints?

A

A plethora of inhibitory pathways (receptors/ligands) hardwired into the immune system to maintain self-tolerance and modulate the duration/magnitude of an immune response (e.g. CTLA4, PD1)

**Cancers can co-opt these to their advantage and inhibit T cells from attacking tumor cells

25
What is the function of checkpoint antibodies?
They are therapeutic antibodies that _block T cell inhibitory receptor signaling_ (**PD1, CTLA4** receptors or PD1 ligand **PD-L1**) allowing T cells to continue functioning \*\*ipilimumab and tremelimumab block CTLA4 (for advanced melanoma; bad autoimmune SE) \*\*PD1/PDL1 blockers have less toxicity (one clinical trial where CTLA4/PD1 blockers are combined)
26
What is adoptive cellular immunotherapy?
Lymphocytes are cultured from tumors (tumor-infiltrating lymphocytes; **TILs**), are expanded in culture, and given back to patients in _large numbers of highly activated T cells that recognize cancer_ \*\*bypasses the tumor suppressive mechanisms \*\*SE: vitiligo (loss of skin pigmentation)
27
Describe CAR therapy
"Chimeric antigen receptor" therapy; T cells collected, expanded/genetically modified, and returned to the patient \*\*type of adoptive cellular immunotherapy, "harnesses the power of both B and T cells"
28
What are the risks with CAR therapy?
1. T cells are so strongly activated they can make large amounts of pro-inflammatory cytokines -\> "toxic shock-like" syndrome 2. If the tumor antigen is also expressed on normal tissues, there could be autoimmune toxicity 3. Tumor antigen may be lost 4. Does not work well for treating solid tumors
29
What is allogenic T cell therapy?
"Graft versus tumor effect" **Donor T cells** are tranferred to the patient (along with hematopoietic stem cell graft), become activated to host alloantigens, and _eliminate residual host cancer cells expressing the alloantigens_ \*\*Activated donor T cells can also cause graft vs host
30
What are bispecific antibodies?
"BiTEs"; Bispecific T cell Engagers Antibodies that bind two targets and in doing so _direct T cells to target molecules_ (redirected lysis)
31
What are the main agonist antibodies to co-stimulatory receptors?
CD40, CD137, ICOS, CD28, OX40 \*\*"normal" ligand is relatively absent in hosts with tumors so _agonist antibodies artificially replace them in order to re-activate T cells_ \*\*this therapy only works with close to normal T cell levels
32
Describe how peptide vaccines can be used against cancer
Tumor cells are removed from the patient, peptides extracted/artificially synthesized, adjuvant is added, and the mixture is given back to the patient \*\*short lived effects (peptides digested) and adjuvant can be toxic
33
Describe dendritic cell vaccines
Immature DCs are "pulsed" (incubated) with tumor antigens or genetically modified to express tumor antigens and then administered to the patient to boost their immune response \*\*DCs can be difficult to grow in culture
34
Describe the two ways DNA vaccine can help the immune response against cancer
1. Indirect route (DNA _vaccine uptake by non-DC cells_, they begin _cross-presenting_ the tumor DNA, and are recognized/taken up by DCs and tumor antigen presented to T cells) 2. Direct route (DNA vaccine uptake by DCs at the injection site and vaccine-encoded tumor antigen is presented to T cells) \*\*DNA itself stimulates the immune system because it's often an indicator of cell injury/death
35
Describe whole cell tumor vaccines
Tumor cells are removed from patient, cultured/genetically modified, and large doses are re-injected to the patient \*\*cells won't grow but _provide a source of tumor antigen to boost the natural T cell response_
36
How are antibodies designed to target tumor antigens?
* block cell survival signals (e.g. anti-HER2) * completment dependent cytotoxicity * Ab dependent cellular toxicity ("bridge" tumor cell and NK cell; proximity aids in killing) * direct apoptosis * toxin delivery
37
What can cancer antigens consist of?
* mutated self proteins * mutated tumor suppressor genes/oncogenes * overexpressed/abberrantly exptressed self proteins * oncogenic viral proteins * post-translationally modified self proteins
38
List some suppressive factors that cancer cells produce in order to decrease the immune response
PGE2, IDO, iNOS, arginase, CSF-1, IL1beta, IL4, IL10, IL13, PD-L1

FPP: pre-midterm (19 decks)

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