Tumor Immunology and Immune Therapies

Question 1

what is immune therapy?

Answer 1

manipulation of the immune system for therapeutic benefit; in this context, use the immune system to help fight cancer

Question 2

what is the immune system?

Answer 2

an immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells

Question 3

what is the main focus for tumor immunology (currently)?

Answer 3

t-cells

Question 4

what are granulocytes

Answer 4

most common: neutrophils (polymorphonuclear cells)

rapidly migrate to sites of inflammation

primary function is to destroy pathogens and tumor cells

Question 5

what is the role of monocytes?

Answer 5

monocytes: circulate in blood and then go to tissue and differentiate into macrophages

macrophages are long lived (2-4 months)

engulf pathogens, dead cells, tumor cells
secrete cytokines and chemokines
present antigens (tell other cells to come)

Question 6

role of natural killer cells

Answer 6

activated by encounter with infected cells or tumor cells

kill target cells

secrete IFN-gamma

Question 7

what are the types of T cells

Answer 7

CD4+: helper T-cells

CD8+: cytotoxic T-cells

Question 8

describe the role of inflamamtion in relation to tumors. how can you tell what type of inflammation it is?

Answer 8

acute inflammation: in tumors results in destruction

• within min…signs: swelling and heat
• vasodilation, vascular permeability
• leads to recruitment of neutrophils

chronic inflammation: contributes to tumorigenesis

• fibrosis, angiogenesis, tissue remodeling
• leads to recruitment of macrophages and lymphocytes

Question 9

asbestos and mesothelioma

Answer 9

asbestos: mineral silicate; cannot destroy it
macrophages phagocytose the fibers from asbestos and this induces chronic inflammation (recruitment of macrophages)

example of how inflammation can cause a tumor

Question 10

what are the 3 E’s of tumor immunology and what is it used for

Answer 10

1. Elimination (immune surveillance)
   - check on health of all cells -> recognize and destroy tumor cells before they become harmful
   - t cells recognize tumor antigens presented by MHC
   - MHC is expressed by tumor cells or macrophages/dendritic cells
   - CD8+ t cells and NK destroy the tumor cells
2. Equilibrium
   - when lymphocytes can no longer destroy the tumor, there is a prolonged period in which tumors remain but do not grow
3. Escape
   - selection of tumor cells that evade immune-mediated destruction; ie tumor cells that lack antigens recognized by CD8+ t cells grow into cancer
   - development of “immunosuppressive” microenvironment
   - some tumors eventually escape immunologic control/checkpoints

immunoediting

Question 11

what is the evidence for the immune surveillance model

Answer 11

1. histopathologic and clinical observations: lymphocytic infiltrates around some tumors and enlargement of draining lymph nodes correlates with better prognosis (the more immune cells you have the better off you are) -> immune responses against tumors inhibit tumor growth
2. experimental: transplants of a tumor are rejected by animals previously exposed to that tumor; immunity to tumor transplants can be transferred by lymphocytes from a tumor-bearing animal -> tumor rejection shows features of adaptive immunity (specificity, memory) and is mediated by lymphocytes
3. clinical and experimental: immunodeficient individuals have an increased incidence of some types of tumors -> the immune system protects against the growth of tumors (“immune surveillance”)

Question 12

how do t cells recognize tumor cells?

Answer 12

via their t-cell receptors (TCR)

antigen, peptide derived from degraded protein, must be presented by MHC (major histocompatibility complex)

tumor cell express MHC Class I or are engulfed by macrophages and dendritic cells, which express MHC Class I and II

Question 13

what are the types of MHC

Answer 13

class I: expressed by most nucleated cells; peptides presented to CD8+ t cells

class II: expressed by professional antigen presenting cells (APCs) -> macrophages, dendritic cells, B cells; peptides presented to CD4+ t cells

Question 14

what are some examples of tumor antigens recognized by T cells?

Answer 14

• oncogenic virus (HPV)
• over-expressed/aberrantly expressed self protein (tyrosinase)
• product of oncogene or mutated tumor suppressor gene (BCR/ABL, mutated p53)
• mutated self protein

Question 15

how are tcells activated? what happens if only signaling happens?

Answer 15

requires TCR + co-receptors (CD28 on T cell; binds to B7) + cytokines (released after co-receptor binds)

signaling via receptor only: anergy = a state of unresponsiveness

TCR + co-receptor results in activation and differentiation

Question 16

how are natural killer cells regulated?

Answer 16

• activating receptors (AR) recognize a variety of ligands on target cells
• inhibitory receptors (KIR) recognize non-polymorphic residues on MHC class I

inhibitory signal is dominant over activating signal

loss of MHC-I on a target cell releases inhibitory signal and permits NK cell activation…if no class I MHC, which is what tumor cells like to do, NK cells are activated

Question 17

difference between CD8+ t cells and NK cells

Answer 17

both occur during elimination phase, are cytotoxic lymphocyte

CD8+ t cells recognize peptide MHC class I complexes

NK cells recognize a lack of MHC class I (which tumor cells often down-regulate)

Question 18

what is the immunosuppressive microenvironment

Answer 18

an environment that will suppress the immune response; contains:

1. regulatory T cells - suppress the activity of T cells, macrophages and other immune cells
   ex: CD4+ t cells that express high levels of FoxP3 TF and CD25
2. loss of MHC expression
3. lack of co-receptor ligation

Question 19

immunologic checkpoints - main concept and important proteins

Answer 19

main concept: t cell exhaustion

• repeated stimulation of t cells results in anergy
• two important inhibitory co-receptors are:
  1. CTLA-4: only want on activated T-cells; binds B7-1/2 and blocks CD28 co-stimulation; anti-CTLA-4 (ipilimumab/Yervoy) blocks CTLA-4 from binding to B7-1/2 (metastatic melanoma)
  recall: normally CD28 binds to B7-1/2 and activates T cells
  2. PD-1: inhibitory co-receptor on t cells; binds PD-L1 and PD-L2 (expressed on dendritic cells); anti-PD-1 (nivolumab) re-activates t cell (clinical trials for malignant melanoma)

Question 20

how can you stimulate the immune system?

Answer 20

1. IL-2 (cytokine)
2. BCG therapy (Bacillus Calmette-Guerin) -> intravesicular instillation for bladder cancer; induces granuloma formation and t cell activation…want to start acute inflammation (which is the granulomas)

Question 21

describe strategies to enhance anti-tumor immune responses

Answer 21

1. passive immunity: immune components (antibodies or cells) that are harvested form one individual and administered to another -> inject patients with monoclonal antibodies against tumor antigens
   a) depleting antibodies, such as anti-CD20; mechanism of action: deplete target cells
   b) functional alterations, such as anti-VEGF; mechanism of action: blocks VEGF from binding receptors, preventing proliferation
   c) toxin-conjugated antibodies, such as ricin or radioactive particles linked to antibodies against GD2
2. active immunity: de novo immune response generated as a result of infection or immunization
   a) vaccinate with tumor antigens (inject tumor antigens with adjuvants)
   b) immunize with tumor cells expressing co-receptor ligands
   c) DNA vaccines/dendritic cell-based vaccination