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Found. of Path. Processes - Block 1 > 14 - Tumor Immunity > Flashcards

14 - Tumor Immunity Flashcards

1
Q

Early evidence exists that the immune system can recognize cancer as ________. How is this possible?

A

Foreign.

Immune system can recognize tumor “altered self” antigens.

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2
Q

Higher amounts of what are correlated with a better prognosis when someone has a tumor? What else do we know about the immune systems role in cancer?

A

Higher T cell infiltration.

Tumor transplants are rejected by already-exposed animals due to an adapted immune memory mediated by T cells.

Immunodeficient individuals have an increased incidence of some tumors.

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3
Q

What is Kaposi’s sarcoma? Who does it occur in?

A

Most common human immunodeficiency virus (HIV)-associated neoplasm.

Pathogenesis involves interaction between human herpes virus 8, inflamm cytokines, and angiogenic factors in the context of profound immune suppression.

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4
Q

If the immune system can recognize abnormal tumor cells, then why does cancer occur in individuals with a normal immune system? (ie how does the immune system shape how cancer progresses?)

A
  1. Eliminataion and equilibrium: immune system activated to kill tumor cells and eliminate tumor. Immune responses frequently fail to prevent tumor growth.
  2. Escape: occurs due to the processes that are designed to prevent “self” reactivity (ie the cells that dampen our immune response in an autoimmune scenario)
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5
Q

How is the adaptive immune system involved in tumor elimination?

A
  1. Helper Th1 CD4+ T cells: provide stimulatory cytokines (IL-2 and IFN-Y)
  2. Cytotoxic CD8+ T cells: kill with granzyme and perforin
  3. B cells: soluble anti-tumor IgG and IgM and complement-mediated killing
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6
Q

What four signals are required to produce activated effectied anti-tumor T cells (CD8) cells?

A
  1. TCR engagement with MHC 1 on APC
  2. Co-stim ligands (CD80-CD86 on APC) with activating receptor (CD28 on T cell)
  3. Effector/memory cytokines (IFN-Y, IL-2, IL-15, IL-7, IFNa/B, IL-12)
  4. Up-regulation of chemokine receptors required for T cell trafficking
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7
Q

Tumor antigens are _________ to CD4 and CD8 T cells by _____ and ______ professional APCs such as dentritic cells.

A

Tumor antigens are cross-presented to CD4 and CD8 T cells by activated and mature professional APCs such as dentritic cells.

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8
Q

Activated and expanded CD8 T cells can do what?

A

Directlty see MHC 1/peptide (tumor antigen) on tumor cels and NO LONGER requires the presence of co-stimulatory proteins.

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9
Q

What four cells types of the innate immune system aid in tumor elimination?

A

YdeltaT cells: recognize antigens expressed by tumor cells

NK cells: produce IFN-Y

Dendritic cells: secrete IL-12 and Type 1 IFNs and cross-present tumor antigens to CD8 cells (immature DCs are tolerogenic)

Macrophages: release pro-inflamm tumorcidal mediators but also mediators that can be pro-tumorigenic

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10
Q

What do M1 macrophages release? What about M2?

A

M1: high IL-12 and low IL-10 > anti-tumor

M2: low IL-12 and high IL-10 > pro-tumorigenic

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11
Q

What is the function of anti-tumor cytokines IFN-Y, IFNa/B, and IL-12?

A

IFN-Y: activates mø and induces MHC class II (made by NK and T cells)

IFN a and B: influence activation of innate and adaptive immunity

IL-12: stimlulates production of IFN-Y and TNF from T cells to enhance cytotoxicity

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12
Q

What is the function of anti-tumor cytokines NKG2D, TRAIL, and perforin?

A

NKG2D: stimulatory receptor, ligand overexpressed by infected, transformed, or stressed cells

TRAIL: death receptor expressed on activated T cells

Perforin: cytolytic mediator made by CD8+ cells

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13
Q

What barriers prevent us from getting rid of cancer?

A
  1. Immune suppressive cell types
  2. Intrinsic suppressive T cell mechanisms
  3. Immune inhibitory factors in the tumor microenvironment
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14
Q

What are immune suppressive cell types that cancer uses to inhibit our immune susyem?

A

Immature/tolerogenic DCs: cannot activate T cells and actively shut them down

Myeloid suppressor cells: kill T cells when they encounter them

M2 macrophages: make immunosuppressive cytokines (IL-10)

T regulatory cells: shut down the immune system

Th2 CD4+ T cells: provide cytokines not good for CTL activity

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15
Q

M1 macrophages are pro_____, while M2 macrophages are pro-_____.

A

M1: pro-inflammatory

M2: pro-growth for the tumor

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16
Q

_____ expansion causes tumors to shrink

A

CTL (cytotoxic lymphocytes)

17
Q

What are the ways that we can “ramp up” T cells in order to target cancer?

A
  • Block the T cell inhibitory (checkpoint) receptors using blocking Abs
  • Transfer of tumor-specific T cells
  • Genetically chnge T cells to cell transfer (chimeric antigen receptors or CAR T cells)
  • Allogenic T cells for anti-leukemia effect
  • Bispecific antibodies
  • Agonist Ab to co-stim T cell receptors
  • Peptide, dendritic cell, and DNA vaccines
  • Immune stimulatory agents
18
Q

How can monoclonal Ab be used to fight cancer? What are two examples?

A

They can be used to block immune checkpoints (inhibitory pathways that modulate the immune response)

CTLA4 blocking antibodies and PD-1 blocking antibodies: these inhibit an inhibitor and activate T cells

19
Q

What is adoptive cellular immunotherapy using tumor-infiltrating lymphocytes (TILs) and how is it used to fight cancer?

A

Culturing lymphocytes from tumors during surgery (tumor infiltrating lymphocytes).

These can be expanded in culture then given back to pts to provide large numbers of highly activated T cells that can recognize cancer. (this is a way to bypass the tumor suppressive mechanisms)

20
Q

What is an example of the immune system targeting non-mutated self-antigens overexpressed on cancer cells?

A

Melanoma patients who have responsed to tumor infiltrating lymphocyte (TIL) therapy usually develope non-life threatening vitiligo (loss of skin pigmentation) and sometimes uveitis due to melanocyte reactivity.

21
Q

What is adoptive immunotherapy using CAR T cells?

A

Chimeric antigen receptor (CAR) therapy simialr to an autologous BMT.

T cells collected from patients and genetically modified and can now recognize the same antigen and become very strongly activated when the antibody portion of the receptor binds to its antigen.

22
Q

How are allogenic T cells (Hematopoietic stem cell transplantation) used as cancer immunotherapy?

A

Donor T cells are transferred to the host (patient) along with the hematopoietic stem cell graft become activated to host alloantigens.

While these activated donor T cells can attack host tissues and cause GVHD (bad), they can also eliminate residual host cancer cells that express alloantigens (good).

23
Q

What is the funciton of bispecific T cell engagers (BiTE)? What does this bypass?

A

Engineered three-pronged bispecific Ab that engages the tumor cell with one arm and activates a T cell (to kill the tumor cell) with the other arm.

This bypasses MHC class II presentation.

24
Q

What is the function of agonist antibodies on co-stimulating molecules? What is a limitation of this method?

A

Directly bind receptors and induce a confirmational change to activate T cells (in the absence of ligand)

Limitation - if a patient has low T cell numbers, then these may not work well because it’s a numbers game and you still need other signals to expand these T cells.

25
Q

How do peptide vaccines work to treat cancer?

A

Tumor cells removed, peptides extrated, adjuvant is added and then the “vaccine” is given.

It activates CTLs that can then kill the tumor.

26
Q

How are dendritic cell vaccines made and how do they work? What does this method bypass? What is one limitation to this method?

A

Dendritic cells incubated with tumor antigens or gentically modified to express tumor antigens. Then given to patient where they can present tumor antigen to T cells.

Bypasses need for endogenous APCs in the body (b/c APCs in patient may be dysfuncitonal)

These can be difficult to grow in culture.

27
Q

How are DNA vaccines made and how do they work?

A

You can design DNA that encodes tumor antigen and inject the naked DNA into pt. Then two things can happen:

  • Vaccine can be taken up by dendritic cell (APC) and presented to T cells
  • Vaccine taken up by non-DC cell and the peptide can be cross-presented to DC cell
28
Q

How are whole cell tumor vaccines made and how do they work?

A

Take tumor cells containing tumor antigens and grow these ex vivo into billions of cells.

After irradiation, these make a good vaccine because they are immunogenic and can be put back into the host to activate CTLs.

29
Q

What are the five methods that Ab can use to target tumor antigens?

A
  1. Blocking cell surivival signals: Trastuzumab (anti-HER2)
  2. Complement dependent cytotoxicity: Ritbuximab (anti-CD20)
  3. Antibody dependent cellular cytotoxicity
  4. Direct apoptosis
  5. Toxin delivery
30
Q

Cancer antigens consist of what five things?

A
  • Mutated self proteins
  • Mutated tumor supressor genes or oncogenes
  • Overexpressed or aberrantly expressed self proteins
  • Oncogenic viral proteins
  • Post-translationally modified self proteins
31
Q

In addition to the required stimulation and co-stimulation needed to activate T cells, _____ _____ ____ cytokines and up-regulation of chemokine receptors is required to produce an effective CTL response.

A

Effector Th1 “helper” cytokines

32
Q

What are the six mechanisms that can activate anti-tumor immunity? Name examples of each.

A
  1. Boosting T cell activation (checkpoint blockage)
  2. Delivering tumor-reactive T cells (adoptive cell transfer, allogenic T cells for leukemia, CAR T cells)
  3. Increasing presentation of tumor antigens (vaccines and antibodies that directly target the tumor or killing)
  4. Augmenting T cell trafficking to the tumor target (bi-specific antibodies-BiTEs)
  5. Boosting innate immunity (TLR agonists)
  6. Blocking immuen suppressive factors/cells (IDO inhibitors)

Found. of Path. Processes - Block 1 (18 decks)

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