Module 05 - Cancer Immunology

Question 1

Why is the immune system thought to have a dynamic role in cancer development?

Answer 1

It can both destroy cancer cells and influence the development of aggressively malignant cells

Question 2

What is immunosurveillance?

Answer 2

The immune system is continuously surveying dividing cells and ensuring they are functioning normally. If not, they are destroyed.
Evidence shows that people who have AIDS (immunocompromised) develop tumours more frequently than people with fully functioning immune system

Question 3

What is the role of the immune system in tumour destruction?

Answer 3

Immune system involved in the regression of tumours
Evidence in support of this theory is that lymphocytes found in tumours have the ability to recognize tumour antigens and malignancies have been shown to regress spontaneously

Question 4

What is the role of the immune system in tumour progression?

Answer 4

The immune system is involved in the progression of tumours. Evidence suggests that chronic inflammation promotes malignancies

Question 5

What is immunoediting?

Answer 5

Modified immunosurveillance theory. describing how the immune system can destroy cancer cells and/or act as selective pressure to drive cancer evolution (eg immune system “edits” cancer). Its a more accurate description of the immune system’s role in cancer development. The fact that cancer can be transmitted through organ transplant supports this theory.

Question 6

What was the historical perspective on immune surveillance in 1909?

Answer 6

Paul Ehrlich first suggested that, without the immune system, it is very unlikely that any of us could live without contracting cancer

Question 7

What did Paul Ehrlich suggest on immune surveillance?

Answer 7

Without the immune system, it is very unlikely that any of us could like without contracting cancer

Question 8

What was the historical perspective on immune surveillance in 1950?

Answer 8

Lewis Thomas and Frank Macfarlane Burnet proposed the concept of immunological surveillance of cancer
Burnet: in large long-lived animals, like most of the warm blooded vertebrates, inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent a step toward malignancy. It is an evolutionary necessity that they should some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character/

Question 9

Who proposed the concept of immunological surveillance of cancer?

Answer 9

Lewis Thomas and Frank Macfarlane

Question 10

What was the historical perspective on immune surveillance in 1970?

Answer 10

Stutman reported that cancer susceptibility of immune competent mice to spontaneous and carcinogen-induced tumours was similar to that of nude (immunoincompetent) mice that had major but not total immunodeficiency.
Led to the abandonment of immune surveillance theory. Supported by arguments that cancer cells did not have proper danger signals needed to alert the immune system, , the immune system is tolerant to a developing tumour because tumour cells were too similar to the normal cells from which they were derived, that activation of innate immunity and inflammation facilitates cellular transformation and promotes tumour growth

Question 11

Whose work led to the abandonment of the immune surveillance theory in the 1970?

Answer 11

Stutman

Question 12

What was the historical perspective on immune surveillance in 2005?

Answer 12

Arguments against immune surveillance of spontaneous cancer were based on the observation that immunogenic tumours evde immune destruction by inducing T cell tolerance

Question 13

What was the historical perspective on immune surveillance in 2010s?

Answer 13

Notion of immune surveillance has currently been accepted as a component of the role of the immune system in cancer development. It fits into the larger picture of immunoediting, which more accurately describes the immune system’s ability to destroy growing cancer cells via immunosurveillance, and promote tumour growth in the cells which evade destruction

Question 14

What does the immunoediting hypothesis stress?

Answer 14

The dual host-protective versus tumour-sculpting roles of the immune system. It also offers an explanation for the selection of less immunogenic tumour cell variants that avoid recognition and destruction by cytotoxic cells of the immune system, thereby contributing to malignant progression

Question 15

What are the 3 phases of immunoediting?

Answer 15

(1) Elimination
(2) Equilibrium
(3) Escape

Question 16

Describe the elimination phase of immunoediting

Answer 16

The innate and adaptive immune systems work in tandem to eliminate tumour cells before they become clinically apparent
- Likely that innate immune cells recognize the damage or danger associated molecular patterns (DAMPs) and produce interferon molecules (IFN-y) which are immunomodulatory molecules that activate dendritic cells and promote the induction of adaptive immune responses

Question 17

What evidences support the elimination phase of immunoediting?

Answer 17

• -There is an earlier onset or deeper penetration of neoplasias in mice that are missing particular immune cell subsets, cytokines, effector pathways, and recognition molecules
• • spontaneous regression of tumours

Question 18

What are the 4 steps of the mechanism of elimination?

Answer 18

(1) Cytotoxic lymphocytes recognize its target cell and forms an immunological synapse. The microtubule organizing centre (MTOC) or the cytotoxic lymphocyte moves to one side of the cell
(2) MTOC facilitates the movement of secretory granules towards the presynaptic membranes
(3) The secretory granules fuse with the presynaptic membrane and release perforin and granzymes into the synaptic cleft. at the post synaptic membranes (cancer cell membrane) the perforin forms large transmembrane pores that enable the diffusion of granzymes into the target cell cytosol
(4) Granzymes then initiate apoptosis of the target cell, and the cytotoxic lymphocyte detaches from the dying cell and can interact with another target cell to carry out serial killing

Question 19

Describe the equilibrium phase of immunoediting

Answer 19

The cancer cells undergo a period of dormancy, a phase of dynamic equilibrium in which tumour outgrowth is suppressed by the immune system

Question 20

What is the longest phase of immunoediting?

Answer 20

equilibrium

Question 21

What evidence the existence of an equilibrium phase ?

Answer 21

Immunocompetent mice were treated with low-dose carcinogens and were found to have “occult” (no clinical symptoms) cancer cells even though there were no apparent tumours present
– When T cells and IFN-y were depleted in these mice by administering monoclonal antibodies tumours rapidly appeared at the original site of carcinogenesis injection and were immunogenic

Question 22

Which immune cells and cytokines are responsible for immunologic dormancy?

Answer 22

IL-12
CD4+
CD8+

Question 23

Describe the escape phase of immunoediting

Answer 23

Characterized by tumour cells that are capable of evading immune recognition or destruction and emerge as progressively growing visible tumours

Question 24

What is one reason for the transition from the equilibrium phase to the escape phase?

Answer 24

Tumour cells have mutated

Question 25

What are the characteristics of the tumour cell variants of the escape phase of immunoediting?

Answer 25

- decreased expression of tumour antigens or antigen immunogenicity - increased resistance to the cytotoxic effects of immune effectors (eg: through increased resistance to pro-apoptotic signals - the immune system has been inhibited by immunosuppressive molecules (eg: vascular endothelial growth factor, or VEGF)

Question 26

What has become accurate prognostic markers of cancer?

Answer 26

Lymphocytes types & density Quantity, quality and spatial distributiom Supporting evidence: studies in ovarian and other cancers demonstrated that it was the ratio of intratumoural CD8+ T cells to Treg cells that was a critical determinant of prognosis

Question 27

What are 4 immune escape mechanisms used by cancer cells?

Answer 27

- loss of tumour antigen expression - resistance to death signals - release of immunosuppressive molecules - activation of immune checkpoints

Question 28

How are cancer cells able to evade the immune system through the loss of antigen expression

Answer 28

- Through the emergence of tumour cells that lack expression of strong rejection antigens - Through the loss of antigen processing function within the tumour cell that is needed to produce antigenic peptide epitope and load it onto the MHC class I molecule - Through loss of antigen-presenting function, which can be MHC-dependent or -independent

Question 29

Describe the MHC-dependent loss of surface antigen escape mechanism

Answer 29

``` Loss or decreased MHC class I expression is associated with invasive and metastatic lesions - likely because MHC class I downregulation leads to lack of recognition by cytotoxic T cells This decreased expression can arise in tumour cells due to mutations that transports the MHC proteins into the ER for processing and transport to the cell surface ```

Question 30

Describe the immunodominance theory in MHC-independent loss of antigen

Answer 30

Associated with disease progression - Preferential immunodetection of one or a few epitopes among many expressed on a given target - Parental tumour cells that carry the immunodominant epitope serve as a red flag, diverting the attention away from the tumour cells with loss of antigen expression - When parental cells are eliminated a new hierachy is established

Question 31

Describe the mechanism behind the loss of surface antigen expression in a MHC-independent fashion

Answer 31

Involves the shedding of Major Histocompatibility Complex Class I Chain-Related (MIC) Molecules from the tumour cell surface There are 2 MIC molecules; MICA and MICB - Expression is induced by cellular stress and up-regulated in many carcinomas - Binding of MICs to the activating receptor NKG2D activates NK cells and augments antigen-specific cytotoxic T lymphocytes anti-tumour immunity The MIC-NKG2D system participates in epithelial tumour immune surveillance Tumour cells evade MIC-NKG2D-mediated immunity by shedding MIC from the cell membrane

Question 32

Explain the MICA-NKG2D mediated immunity and how tumour cells evade it

Answer 32

- NK cells have NKG2D on their cell surface which binds to MICA on tumour cells - Secretion of tumour lysis inducing factors such as perforin, granzyme, and cytokines. Results in tumour death - Tumours evade destruction by NK cells by shedding MICA receptors from their surface

Question 33

How does loss of tumour antigen expression contribute to immune escape

Answer 33

Decreased recognition and destruction by effector cells from both the innate and adaptive arms of the immune sytem

Question 34

How does hypoxia facilitate immune evasion?

Answer 34

Hypoxia increased the shedding of MICA from tumour cells thereby increasing their ability to evade NK cell-mediated lysis

Question 35

What are some mechanisms used by tumour cells to resist death signals? (3)

Answer 35

- Induction of anti-apoptotic mechanisms involving persistent activation of pro-oncogenic transcription factors such as STAT3 - Expression of anti-apoptotic effector molecules such as BCL-2 - Downregulation of apoptosis-inducing receptors such as FAS and TRAIL

Question 36

What are 3 ways tumours cells can avoid apoptosis through defective death receptor signals

Answer 36

- Mutations in FAS and TRAIL receptors themselves - Mutations in elements of the proximal pathway )Fas Associated Death Doman (FADD), caspases) - Up-regulation of c-FLIP, a caspase-8 inhibitor

Question 37

What are the 3 types of immunosuppressive molecules released by tumour cells?

Answer 37

Cytokines Enzymes Prostalglandins

Question 38

What are the immunosuppressive cytokines released by tumour cells?

Answer 38

VEGF IL-10 TGF-beta

Question 39

What is the role of VEGF as as immunosuppressive cytokines released by tumour cells

Answer 39

angiogenesis, inhibits dendritic cell differentiation and maturation

Question 40

What is the role of IL-10 as as immunosuppressive cytokines released by tumour cells

Answer 40

inhibits dendritic cell differentiation, maturation, and function reduces IL-12 production dampens antigen presentation and Th1 cells responses increases susceptibility of NK cells to lysis

Question 41

What is the role of TGF-beta as as immunosuppressive cytokines released by tumour cells

Answer 41

positively correlated with disease progression | Inhibits the activation, proliferation, and function of lymphocytes

Question 42

What are the immunosuppressive enzymes released aiding in evasion of tumour cells + the cells that produce them? (3)

Answer 42

Indoleamine 2,3-dioxygenase (IDO) (tumour cells and infiltrating myeloid cells) Arginase (myeloid-derived suppressor cells)

Question 43

What is the main way immunosuppressive enzymes exert their function in tumour cells evasion?

Answer 43

Local depletion of amino acids essential for lymphocyte function (particularly T cells)

Question 44

WhWhat is the immunosuppressive prostalglandins released aiding in evasion of tumour cells + the cells that produce them?

Answer 44

E2 | Many inflammatory cells

Question 45

What are prostalglandins?

Answer 45

fatty acids that have diverse hormone-like effects in human cells

Question 46

What are immune checkpoints and why are they important to health states?

Answer 46

They are inhibitory pathways critical for self-tolerance and for modulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage Without immune checkpoint mechanisms, the immune system could also damage healthy tissue

Question 47

What are the two immune checkpoints co-opted by tumour cell for immune evasion?

Answer 47

CD28/CTLA4 | PD-1/PD-L1

Question 48

How does CTLA-4 works in healthy cells?

Answer 48

- Predominantly expressed in CD4+ helper T cells - Inhibits CD28-mediated co-stimulation of T cells by competing for binding to CD80 and CD86 present on antigen-presenting cells (APCs) - CTLA-4 also interferes with the TCR stop signal, which maintains the immunological synapse long enough for extended or serial interactions between the TCR and its peptide-MHC ligand - Knockout of CTLA-4 leads to lethality due to systemic immune hyperactivation

Question 49

How does tumour manipulate CTLA-4?

Answer 49

- Tumour cells take advantage of inhibitory pathway by constitutively expression CTLA-4 - Induces suppressiong of CTLs - Suppression of anti-tumour immunity resides primarily in secondary lymphoid organs, rather than within the tumour microenvironment (TME)

Question 50

How does Programmed Death 1 (PD-1) work in healthy cells

Answer 50

PD-1 pathway limits the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity. - PD-1 receptors is expressed on activated T cells, B cells, NK T cells, activated monocytes, and dendritic cells (DCs) - -- It binds to the Programmed Death Ligands 1 & 2 (PD-L1/L2) - PD-L1 expression is induced on activated hematopoietic cells and on epithelial cells by the inflammatory cytokine interferon (IFN-gamma) - PD-L2 espression is limited to activated DCs and some macrophages - Binding of PD-L1 to PD-1 on T cells results in T cell dysfunction (apoptosis, exhaustion or anergy) and consequently, inhibition of adaptative anti-tumour immunity - PD-1 is also expressed on Treg cells but it enhances their proliferation in the presence of ligand

Question 51

How does tumours use PD-1 to their advantage?

Answer 51

- PD-L1 expression can be induced in tumour cells by interferon-gamma, but can also be upregulated due to mutation or gene amplification - - Expression can be driven by oncogenic signalling pathways in the tumour cell - Tumour cells PD-L1 expression is also induced by hypoxia - PD-L2 is highly expressed in a subset of B cell lymphomas - PD-1/PD-L1 checkpoint operates primarily within the tumour microenvironment where PD-L1 is commonly expressed by tumour and infiltrating leukocytes

Question 52

Where does CTLA-4 exert its effect?

Answer 52

prevents T-cells activation in peripheral lymphoid organs

Question 53

Where does PH-1/PD-L1 exert their effect?

Answer 53

T-cell dysfunction within the tumour microenvironment

Question 54

Why are immune checkpoint pathways significant to cancer development?

Answer 54

They each represent a different potential way for tumours to evade the immune system and proliferate

Question 55

What is acute inflammation associated with in cancer??

Answer 55

Protective adaptive immune response to pathogens and cancer - In carcinogen-treated mice, the importance of pro-inflammatory was concluded from the observation that tumour induction required molecules like IL-1 beta, IL-23, and MyD88

Question 56

What is chronic inflammation associated with in cancer?

Answer 56

Tumourigenesis - At the initial state, it can cause genotoxic stress. at the cancer promotion stage, chronic inflammation can induce cellular proliferation. As cancer progresses chronic inflammation can enhance angiogenesis and tissue invasion - it can contribute to the spread of metastasis

Question 57

What are benefits associated with inflammation?

Answer 57

Some pro-inflammatory molecules can also promote induction of tumour immunity depend on when they are recruited during the development of the cancer. EX: IL-1 beta promote the development of immune responses against established tumours by facilitating tumour recognition, but only if present at later stages of tumourigenesis

Question 58

Which cancer are associated with chronic inflammatory diseases?

Answer 58

Colon cancer and inflammatory bowel disease Liver cancer and hepatitis C infection Stomach cancer and heliobacter pylori infection

Question 59

What roles do chemokines play during tumour growth?

Answer 59

- Regulation of tumour growth - Regulation of angiogenesis - Facilitating metastasis

Question 60

How do you think regular Aspirin use contributes to decreased cancer risk, given that, it is an anti-inflammatory?

Answer 60

Some of the positive effects of aspirin have been attribute to its anti-inflammatory and anti-immunosuppressive properties. Most substantial risks reduction in colorectal cancer risk. However, there were no RCT done, only prospective and retrospective studies (cautious optimism) and we need to study if the risk reduction outweighs the side effects of Aspirin (such as GI bleeding)

Question 61

What are types of Active immunotherapy? (5)

Answer 61

1- Dendritic cell-based immunotherapies 2- Peptide and DNA-based anti-cancer vaccines 3- Active immunotherapy secondary to conventional therapy 4- Pattern recognition receptor (PPRs) agonists 5- Immune checkpoint blockade therapy

Question 62

Describe dendritic cell-based immunotherapies

Answer 62

Involves isolation of patient- or donor-based circulating monocytes - Amplification and differentiation of cells occurs ex vivo in the presence of agents that promote DC maturation - DCs are expose to a source of tumour-associated antigens and then re-infused into the patient - DCs are then able to prime tumour-associated antigen (TAA)-targeted immune responses

Question 63

Describe peptide and DNA-based anti-cancer vaccines

Answer 63

Full length recombinant tumour associated antigens (TAAs) or peptides of TAAs are administered to cancer patients (Usually together with an immunostimulatory agent) to stimulate the immune system

Question 64

Describe active immunotherapy secondary to conventional therapy

Answer 64

- Intravesical (inside the bladder) administratoin of Bacillys Calmette-Guérin (BCG), a vaccine use to prevent tuberculosis, can activate the immune system thereby preventing recurrence of bladder cancer after surgical removal of the primary tumour - Some conventional primary therapies such as chemotherapy and radiation therapy elicit long lasting effects (immune responses) via the release of damage-associated molecular patterns (DAMPs) from dying cells. DAMPs bind to receptors on innate immune cells such as monocytes thereby triggering their anti-tumour activation

Question 65

Describe the pattern recognition receptor (PRRs) agonists

Answer 65

- PRRs are evolutionarily conserved proteins involved in the recognition of danger signals - Activation of PRRs by danger signals activates a signal transduction cascade with pro-inflammatory outcomes, activating or re-activating an anti-cancer immune response - Drugs that are agonists of PRRs are used to induce immune response to tumours

Question 66

Describe immune checkpoint blockage therapy

Answer 66

Therapy that releases the brakes on the immune system by reducing impact of checkpoint blockade

Question 67

What are types of Passive immunotherapy?

Answer 67

1- Tumour targeting monoclonal antibodies 2- Oncolytic Viruses 3- Adoptive Cell transfer

Question 68

Describe tumour targeting monoclonal antibodies

Answer 68

Monoclonal antibodies that target and neutralize receptors or tumour-associated antigens present on the surface or malignant cells. These antibodies inhibit signalling pathways required for the survival or progression of neoplastic cells

Question 69

What was the first monoclonal antibody to be licensed for the treatment of non-hodgkin's lymphoma in 1997?

Answer 69

Rituximab, a chimeric antibody specific for the B-cell lineage marker CD20

Question 70

What are current types of current monoclonal antibodies therapy?

Answer 70

there are 15 monoclonal antibodies approved - Antibodies that target proteins preferentially expressed on the surface of cancer cells - Antibodies that target trophic signals provided by the tumour stroma - Antibodies that mediate therapeutic effects by binding to cells of the immune system, thereby activating an immune response against malignant cells

Question 71

Describe oncolytic viruses as therapy

Answer 71

Use of non-athogenic viral strains that specifically infect cancer cells and trigger their demise. They act as vaccines and can be loaded with immunomodulatory genes or combined with other immunotherapies. Specificity is based on the selective replication of oncolytic viruses (OVs) in tumour cells and their subsequent spred within the tumour without collateral damage -- Tumour cells are more permissive to OV infection than normal cells because tumour cells tend to have altered interferon signalling (allowing for immune escape) Can induce anti-tumour immune responses via the release of tumour antigens from lysed cells -- generated an immune response as secondary function; primary function is tumour death via viral-induced lysis

Question 72

Describe adoptive cell transfer as an immunotherapy

Answer 72

- Circulating or tumour infiltrating lymphocytes are collected - Lymphocytes are selected, modified, expanded or activated ex vivo and re-administered to patients in combination with immunostimulatory therapy. - The result: personalized cancer therapy that involves immune cells with direct anti-cancer activity - However, this therapy can be challenging because it is difficult to identify cells that selectively target cancer cells and not normal cells

Question 73

What are some treatment advantages of adoptive cell transfer? (4)

Answer 73

- Can generate large numbers of anti-tumour T-cells - Can be selected for recognition of the tumour, as well as for cytolytic activity required to mediate cancer regression - In vitro activation allows such cells to be released from the inhibitory factors present in vivo - Re-introduced cells can proliferate in vivo and maintain their anti-tumour functions

Question 74

What kind of treatment is chimeric antigen receptor T (CART) cell therapy?

Answer 74

Adoptive cell transfer, passive immunotherapy

Question 75

How does chimeric antigen receptor T (CART) cell therapy work?

Answer 75

- Chimeric antigen receptors (CARs) are proteins engineered to allow T cells to recognize a specific antigen on tumour cells - Patient-derived T cells that express these CARs (CART cells) are expanded in vitro and infused in the patient - - These CART cells then recognize and kill cancer cells that express the specific antigen on their surfaces

Question 76

Which type of cancers does CART cell therapy show promise for?

Answer 76

Blood cancers, including leukemia and lymphoma

Question 77

What are some limitations of CART cell therapy? (3)

Answer 77

- Success of therapy depends on the expression of the chosen antigen in most, if not all, tumour cells - Antigen should not be expressed by normal cells - Success depends on the ability to optimally select genetically engineer cells with targeted antigen specificity and then induce the cells to proliferate while preserving their effector function and engraftment and homing abilities.

Question 78

Describe sipuleucel-T therapy (Provenge)

Answer 78

Autologous to cellular immunotherapy for the treatment of metastatic castrate-resistant (hormone refractory) prostate cancer - Peripheral blood mononuclear cells are obtained by leukapheresis and cultured (activated) with a recombinant human protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. Results from a clinical trial revealed that patients treated with sipuleucel-T had a median overall survival of 26 months compared to 22 months for patients who received control treatment

Question 79

What are the antigen-presenting cells manipulated in Provenge therapy?

Answer 79

Dendritic cells

Question 80

Why does tumour heterogeneity present a problem for targeted therapies?

Answer 80

Because these therapies target specific tumour antigens (eg Sipuleucel T; CART) and work best in homogeneous tumours whereby all (or most) tumour cells express the antigen

Question 81

How does immune checkpoint blockade therapy address tumour heterogeneity?

Answer 81

It involves stimulation of broad anti-tumour immune response (I.e. expansion and activation of multiple clones of immune effector cells that react against multiple tumour antigens)

Question 82

What are the limitations surrounding CTLA-4 blockade therapy?

Answer 82

Only a proportion of patients benefit Slow response Collateral immune toxicities; maanged with steroid and TNF blockers

Question 83

What kind of therapy is ipilimumab?

Answer 83

CTLA-4 blockade therapy

Question 84

Describe CTLA-4 blockade therapy with ipilimumab clinical trials

Answer 84

- enhanced anti-tumour immune responses - 3.5 month survival benefit - 18% of patient survived beyond 3 years - approved for advanced melanoma in 2010

Question 85

How does PD-1/PD-L1 blockade therapy work?

Answer 85

Enhance anti-tumour immune responses by: - antibody blockade of PD1 or its ligands - diminishing the number and/or suppressive activity of intra-tumoural Treg cells - enhancing NK cell activity in tumours and tissues and may enhance antibody production because NK cells and B cells also express PD-1 on the membrane

Question 86

Describe the clinical trial results of PD-1/PD-L1 blockade therapy (Nivolumab and Pembrolizumab)

Answer 86

Approved in treatment of heavily pre-treated metastatic melanoma (2014) and non-small cell lung cancer (2015) - Clinical trials using both antibodies have revealed unprecedented responses with signification progression-free and overall survival - Response rates between 15% and 31%. - better response rates in patients whose tumours expressed higher levels of PD-L1 - Targeting PD-L1 also show promises

Question 87

What are some limitations surrounding PD-1/PD-L1 therapy?

Answer 87

- Immune related adverse events including dermatologic, gastrointestinal, hepatic, and endocrine events; predisposition to opportunistic infections (often successfully treated with corticosteroids without affect therapeutic efficacy) - Only a fraction of patients responds, thus, needing predictive biomarkers of response

Question 88

Which CTLA-4 inhibiting antibody did better in clinical testing? Why?

Answer 88

Ipilimumab did better, but it was likely due to more careful monitoring or dosing and scheduling

Question 89

Why do some tumours increase in size after anti-CTLA-4 therapy?

Answer 89

Hypothesized that it is because of increased immune cell infiltration to the tumour mass

Question 90

How does PD-1 differ from CTLA-4?

Answer 90

The major role of PD-1 is to inhibit activity ot T cells in peripheral tissues during infections to decrease collateral autoimmune reactions. CTLA-4, on the other hand, aims to inhibit T cell activation during major immune responses in peripheral lymphoid organs