L20 Cancer Flashcards
Cancer
Caused by the progressive growth of the progeny of a single transformed cell
Third cause of death after infections and cardiovascular diseases
New treatments urgently required (clinical need)
Translational research (biology and immunology in the laboratory) essential
Cancer therapy
Aim of anti-cancer therapy: remove or destroy the cancer cells (specifically without damaging healthy cells).
Current therapeutic options:
Surgery
Radiation
Chemotherapy
*New therapeutic approach: cancer immunotherapy
Boost the immune response against the tumour Advantage: Specific and could spare healthy cells
Immunotherapy strategies
Adoptive T cell transfer (CAR-T cells)
Drugs od Monoclonal antibodies against tumour antigens -recognise inhibitory receptors of t cells.
Vaccination
Monoclonal antibodies against T cell inhibitory receptors or immune checkpoint ligands (today’s lecture)
t-cell mediated immunity
T cells should kill tumour cells (t-cell mediated immunity)
The cancer cells present tumour-cell antigens. Naturally released. Dendritic cells should take up the antigen, internalise. Travel to lymph nodes where they present antigens to t cells. T cells should become activated to that tumour antigen, proliferate and move to site of tumour. Then kill tumour cell.
(Cancer-immunity cycle: in lymph nodes, dendritic cells (DCs) (APCs) present tumour antigen (Ag) on MHC molecules and activate antigen-specific CD4+ and CD8+ T cells. T cells then traffic to the tumour site (sites of tumour Ag and inflammation) where they can scan fo
r target cancer cells displaying cognate Ag and kill them.)
Tumour antigens?
The tumor antigens recognized by human T cells fall into one of four major categories:
Antigens encoded by genes specifically expressed by tumors
Antigens encoded by variant forms of normal genes that have been altered by mutation
Antigens normally expressed only at certain stages of differentiation or only by certain lineages
Antigens that are overexpressed in particular tumours.
Abnormally expressed or abnormal forms of normal genes or tumour oncogenes- genes elevated in cancer and expressed by many cancer cells.
Immune responses to tumour?
T cell-mediated lysis: T cells directly kill tumor cells (discussed in today’s lecture).
Natural Killer (NK) cell activity: NK cells protect against cancer by recognizing cells that have lost MHC class I, a common occurrence in cancer (covered in a previous lecture).
Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells kill antibody-coated cancer cells.
Macrophage-mediated tumor destruction: Macrophages phagocytose tumor cells.
T cell activation:
T cells recognize tumor antigens (signal 1).
They also receive signal 2, which can be inhibitory or activating, modulating the immune response to cancer.
Tumor immune evasion:
Tumor cells downregulate MHC class I or stop expressing certain proteins to avoid immune recognition.
Cancer cells secrete suppressive factors (e.g., TGF-β) that inhibit T cell activity.
They upregulate inhibitory ligands to suppress immune responses.
Cancer-immunity cycle:
In lymph nodes, dendritic cells (DCs) present tumor antigens on MHC molecules, activating CD4+ and CD8+ T cells.
These T cells traffic to tumor sites where they identify cancer cells displaying the cognate antigen and kill them.
Immune checkpoints:
Tumors exploit inhibitory receptors and ligands (immune checkpoint molecules) to impair T cell survival, activation, proliferation, and effector functions.
Anti-tumor T cells are suppressed by these molecules.
Key immune checkpoint molecules:
Inhibitory ligands: PD-L1, PD-L2.
Receptors: PD-1, CTLA-4.
Defective immune synapses in cancer:
T cells from cancer patients exhibit defective F-actin immunological synapses, reducing their efficiency.
mechanisms by which tumours avoid immune recognition?
How are T cell response kept in check?
Immune homeostasis
T cell activation requires 2 signals to be fully activated. Cd28- a costimulatory receptor expressed on t cell helps activation through signal 2. Cd28 binds to B7 -1 and B7-2 (chatgpt) (cd80, cd86) Ligands expressed on dendritic cells.
T cell activation occurs after interaction between the TCR and antigen (Ag) in the context of MHC (signal 1).
TCR signalling occurs when the TCR is engaged by cognate peptide (Ag)-mhc. Inhibitory receptors like PD-1 and CTLA-4 downregulate T cell activation. PD-1 binds to PD-L1 and PD-L2, ligands often expressed on dendritic cells and tumor cells.CTLA-4 binds to CD80 and CD86, competing with CD28 and delivering inhibitory signals. T cell activation in lymph nodes is finely balanced between co-stimulatory signals (accelerators) and inhibitory signals (brakes) provided by these ligand–receptor interactions.
When T cells become overactivated in lymph nodes, inhibitory receptors like CTLA-4 and PD-1 are upregulated to limit T cell responses and prevent immune overactivity.
When t cells overactivated in lymph nodes the inhibitory receptors have to downregulate t cell activation.
Depicted are the complex ligand–receptor interactions (signal 2) between antigen-presenting cells (APCs) and T cells that regulate the T cell response to antigen (signal 1) (which is mediated by peptide (Ag)–major histocompatibility complex (MHC) molecule complexes that are recognized by the T cell receptor (TCR)). These responses can occur at the initiation of T cell responses in lymph nodes (where the major APCs are dendritic cells, DCs) or in peripheral tissues or tumours (where effector responses are regulated). In general, T cells do not respond to these ligand–receptor interactions unless they first recognize their cognate antigen through the TCR. Many of the ligands bind to multiple receptors, some of which deliver co-stimulatory (+) signals and others deliver inhibitory (-) signals (“immune checkpoint” molecules).
Biology of immune checkpoint CTLA-4
in health (normal immune homeostasis
CTLA-4 engagement down-modulates the amplitude of T cell responses, largely by inhibiting co-stimulation by CD28, with which it shares the ligands CD80 (B7.1) and CD86 (B7.2). - ctla-4 shares and competes for same ligands as cd28.
CTLA-4 has a much higher affinity for both CD80 and CD86 compared to CD28, so its expression on activated T cells dampens CD28 co-stimulation by out-competing CD28 binding (and possibly also via depletion of CD80 and CD86 via “trans-endocytosis”). Ctla-4 activates phosphatases to downregulate t cell activation.
Naïve and resting memory T cells express CD28, but not CTLA-4, on the cell surface, allowing co-stimulation to dominate upon antigen recognition.
However, CTLA-4 is rapidly mobilized to the cell surface from intracellular protein stores, allowing feedback inhibition to occur within an hour after antigen engagement and T cell activation.
CTLA-4 has a central role in maintaining immune tolerance in lymph node tissue.
Biology of immune checkpoint PD-1 in health (normal immune homeostasis)
PD-1 is absent on resting naïve and memory T cells and is expressed upon TCR engagement.
In contrast to CTLA-4, PD-1 expression on the surface of activated T cells requires transcriptional activation, and thus is delayed (6–12 hr after activation).
PD-1 engagement can also activate the inhibitory phosphatase PP2A. PD-1 engagement directly inhibits TCR-mediated effector functions.
`PD-1 has important physiologic role in restraining collateral tissue damage during T cell responses to infection. Prevent t cells from being overactivated.
Basic mechanisms of T cell activation and inhibition
a | T cell activation begins with interaction of the T cell receptor (TCR) on a T cell with major histocompatibility complex (MHC) bound to antigen on an antigen-presenting cell (APC). This is known as signal 1, but appropriate activation of the T cell requires additional signals that are provided by the interaction between CD28 and B7 (signal 2).
b | T cell activation is limited by cytotoxic T lymphocyte-associated protein 4 (CTLA4), which is upregulated on activated T cells, where it outcompetes CD28 for binding to B7 on an APC. Additional regulation of T cell activity is also provided by later inhibitory signals through other molecules such as programmed cell death 1 (PD1), which binds to PD1 ligand 1 (PDL1).
Complex interactions between the co-inhibitory (checkpoint) receptors CTLA-4 and PD-1 and their ligands?
The 2 ligands for PD-1 are PD-L1 and PD-L2 .
PD-L1 is induced on activated hematopoietic cells by cytokine IFN-γ
PD-L2 expressed on DCs and some macrophages
Same for ctla-4 either cd8 or cd26.
How do tumour cells exploit pathways that normally keep T cells in check to suppress CD8+ CTLs?
Immune checkpoint receptors (PD-1, CTLA-4) and their ligands (PD-L1/2) are upregulated in cancer
PD-1 ligands (PD-L1, PD-L2) are upregulated in cancer
PD-1 receptor is highly expressed on T cells from cancer patients (TILs) – chronic stimulation by tumour antigens (Ags) drives “T cell exhaustion”
Co-option of the immune checkpoint network (ligands and receptors) is a central process by which tumours resist elimination by endogenous tumor-specific T cells
In healthy tissues- pdl-1 normally expressed at relatively low levels on dendritic cells?
So increased expression= more pd-1 engaged with the ligand. Interacts much more readily. Ligands can be expressed by tumour themselves or by dendritic cells. Drives immune suppression as if t cell interacts with cancer=suppressed more readily by cancer cells.
Mechanisms of PD-1 induction on TILs (CD8+ CTLs) in cancer?
In addition, tumor infiltrating lymphocytes (TILs) (CD8+ CTLs) commonly express heightened/increased levels of PD-1 and are thought to be “T cell exhausted” due to chronic stimulation by tumour antigens.
Exhaustion or anergy of PD-1+ T cells is a form of inactivation in which the cell remains alive but cannot be activated to execute an immune response. Anergy is a reversible state.
T cell exhaustion- suppressed, not activated or functioning well. T cells no longer kill cancer cells effectivley.
2 mechanisms of PD-1 ligand (PD-L1) induction in cancer
Mechanisms for why the ligands are overexpressed in cancer: cancer cells have oncogenic protein pathways which are activated e.g: akt. When tumour cell has oncogenic signalling, pd-L1 is expressed at very higher levels. Called innate resistance or intrinsic resistance:
Intrinsic resistance refers to the constitutive expression of PD-1 ligands because of genetic alterations or activation of oncogenic pathways in cancer cells.
Constitutive expression of PD-1 ligands - amplification of chromosome 9p24.1 in Hodgkin’s lymphoma which encodes PD-L1, PD-L2 and JAK2.
EBV viral infection is another mechanism of PD-L1 overexpression in the lymphomas.
Alternativley: adaptive resistance. T cell recognises signal 1 and secrete ifn-y which is taken up by tumour cell, triggers stats signalling that elavates pd-L1.
Adaptive resistance refers to the induction of tumour PD-L1 expression in response to cytokine IFN-γ secreted by proximal T cells.
Adaptation of tumor cells upon sensing an inflammatory immune/T cell response.
Inhibition of T cells also mediated by PD-L1+ myeloid cells or DCs in the tumour microenvironment
Adaptive resistance in lymphoma?
Treating leukaemia (CLL) and lymphoma (DLBCL) tumor cells with anti-PD-L1 or T cells with PD-1 prevents tumour inhibitory signalling and rescues anti-tumor T cell activity.
Mechanisms of PD-L1 pathway-induced immunosuppression in the tumour microenvironment
t cell apoptosis, t cell exhaustion, treg induction.
