Tumor Immunology and Immune Therapies Flashcards
what is immune therapy?
manipulation of the immune system for therapeutic benefit; in this context, use the immune system to help fight cancer
what is the immune system?
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
what is the main focus for tumor immunology (currently)?
t-cells
what are granulocytes
most common: neutrophils (polymorphonuclear cells)
rapidly migrate to sites of inflammation
primary function is to destroy pathogens and tumor cells
what is the role of monocytes?
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)
role of natural killer cells
activated by encounter with infected cells or tumor cells
kill target cells
secrete IFN-gamma
what are the types of T cells
CD4+: helper T-cells
CD8+: cytotoxic T-cells
describe the role of inflamamtion in relation to tumors. how can you tell what type of inflammation it is?
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
asbestos and mesothelioma
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
what are the 3 E’s of tumor immunology and what is it used for
- 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 - Equilibrium
- when lymphocytes can no longer destroy the tumor, there is a prolonged period in which tumors remain but do not grow - 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
what is the evidence for the immune surveillance model
- 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
- 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
- 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”)
how do t cells recognize tumor cells?
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
what are the types of MHC
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
what are some examples of tumor antigens recognized by T cells?
- 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
how are tcells activated? what happens if only signaling happens?
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
how are natural killer cells regulated?
- 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
difference between CD8+ t cells and NK cells
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)
what is the immunosuppressive microenvironment
an environment that will suppress the immune response; contains:
- 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 - loss of MHC expression
- lack of co-receptor ligation
immunologic checkpoints - main concept and important proteins
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)
how can you stimulate the immune system?
- IL-2 (cytokine)
- 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)
describe strategies to enhance anti-tumor immune responses
- 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 - 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
