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IMS: Immunology > Cancer > Flashcards

Cancer Flashcards

1
Q

Immune Surveillance

A
  • Immune system patrols for invading pathogens & cells that turn cancerous.
  • Abnormal cells detected and removed by healthy immmune system
  • Tumors can stimulate a protective specific, adpative immune response through tumor specific CD8+ T-cells
  • Malignant cells find ways to escape immune surveillance
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2
Q

Immune Escape

Causes

A
  1. weak immunogenicity of the tumor due to its host origins
  2. rapid growth of the tumor overwhelms the immune system
  3. selective pressures on tumor cells promotes the development of mechanisms for evading host immune responses
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3
Q

Tumor-Specific Antigens

(TSAs)

A

Antigens that are uniquely expressed by tumor cells but not by normal cells.

Sometimes referred to as neoantigens.

Hypothetically, any of these Ag could be recognized by the immune system.

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4
Q

Tumor-Associated Antigens

(TAAs)

A

Normal cellular antigens expressed at higher levels by tumors as compared to normal cells or at different stages of development or differentiation.

  • CA-125 and ovarian cancer
  • PSA and prostate cancer
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5
Q

Biomarker

A

Protein or other component in the body that can be used as a measurable indicator to identify a disease state or assess the severity of the disease.

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6
Q

Cancer Biomarker

A

A biological factor which can be quantitatively measured to yield cancer-related patient information including:

cancer predisposition

early detection

monitoring cancerous growth

selection of treatment

overall prognosis

TAAs and TSAs can be used.

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7
Q

CTLs

A

CTLs

  • Recognize tumor antigens presented by class I MHC.
  • If tumor isn’t cleared, cells may upregulate CTLA-4 causing downgregulation of CTL response.
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8
Q

TH1 Cells

A

TH1 cells

  • Tumor antigen specific
  • Important in initiation of CTL function
  • generate IFN-γ and TNF-α lead to classically activate macrophages
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9
Q

B-Cells

A

B-cells

  • Formation of tumor specific antibodies
    • Promote ADCC by NK cells and macrophages
    • Promote complement-mediated tissue damage and inflammation
    • Passive Ab administration has shown both a therapeutic effect & in some cases was linked to tumor progression
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10
Q

NK Cells

A

NK cells

  • Down-regulation of MHC I by 50% of tumors
  • Loss of MHC I ligand for inhibitory receptor of NK cells results in tumor killing and cytokine production
  • Can kill tumor cells by ADCC
  • Killing enhanced by IFN-γ, IL-12, and IL-15
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11
Q

Classically Activated

Macrophages

A

Classically activated macrophages

  • Stimuated by IFN-γ
  • Kill tumor cells via ADCC
  • Recognize phospholipids ectopically expressed by malignant cells
  • Release lysosomal components and cytokines
    • Can lead to thrombosis in tumor blood vessels
    • Results in inhibition of tumor growth
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12
Q

TH2 Cells

&

Alternatively Activated Macrophages

A
  • TH2 Cells
    • Produce IL-10 and IL-4
    • Leads to alternatively activated macrophages
  • TH2 Cells and alternatively activated macrophages contribute to a microenvironment high in TGF-β and vascular endothelial growth factor (VEGF)
  • Downregulates the immune response
  • Promote tumor angiogenesis
  • Effects could contribute to tumor progression
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13
Q

Tumor Microenvironment

A

The unique cellular composition surrounding the tumor.

Pro-tumor

  • TH2 cells and alternatively activated macrophages
  • Generates an immunosuppresive environment
  • Stimulation of Treg cells
  • Generation of a low level of chronic inflammation

Anti-tumor

  • TH1 cells and classically activated macrophages
  • CTLs
  • B-cells
  • NK cells
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14
Q

Tumor

Decreased Immunogenicity

A
  • Derived from host cells
    • Do not expresses PAMPs
    • Attenuates the anti-tumor innate immune reponse
    • Decreased adaptive immune response
  • High rates of heritable somatic changes due to high mitotic index and genome instability
    • Mutations which result in decreased immunogenicity of tumor cells have selective advantage
  • Antigenic modulation
  • Low levels of MHC Class I expression
  • Decreased expression of adhesion molecules
  • Proteolytic shedding of MIC
    • MIC molecules are a stress-induced “alterer” molecule that can bind to the NK cell activating receptor (NKG2D)
    • Without activating receptor, NK cells fail to get stimulatory signal
    • Lack of MHC I will no longer trigger killing
  • Blocking antibodies
    • Anti-tumor antibodies bound to tumor antigens inhibit CTL function and may inhibit ADCC by NK cells
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15
Q

Tumor

Treated as Self

A
  • Tolerogenic state can be induced by:
    • Failure to induce a robust “danger signal”
    • Poor innate immune response
    • Prolonged antigenic exposure
  • The “danger signal” results in increased B7 and MHC class I & II
    • Allows the effective stimulation and activation of naive T cells
  • If naive T cells encounter tumor antigens without co-stimulation, the tumor specific T-cell could be anergized as part of peripheral tolerance.
  • T-cell activation in the absence of a “danger signal” is likely to result in tumor specific T-reg cells
  • If tumor celsl are not promptly eliminated, tumor antigen specific T-cells can be downregulated by AICD (activation induced cell death) and CTLA-4 up regulation.
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16
Q

Activation Induced Cell Death

(AICD)

A
  • Programmed cell death caused by the interaction of Fas receptors and Fas ligands.
  • AICD is a negative regulator of activated T lymphocytes that results from repeated stimulation of their T-cell receptors (TCR)
  • Helps to maintain peripheral immune tolerance.
  • Both activated T cells and B cells express Fas and undergo clonal deletion by the AICD mechanism.
  • Activated T cells that express both Fas and FasL may be killed by themselves or by each other.
17
Q

Tumor-Induced

Immune Suppression

A

Tumors can express or secrete factors that alter the immune response.

  • Inhibitory cytokines
    • TGF-β and/or IL-10 produced by many tumors
    • Combination inhibits the immune response
    • Promotes alternatively activated macrophage function
    • Increases angiogenesis
  • FasL expressed by some tumors
    • Binds to Fas on leukocytes recruited to the tumor
    • Causes death of the attacking cells
  • Programmed Cell Death-ligand-1 (PD-L1) expressed by tumor cells
    • Binds to the PD-1 on activated T cells, B cells, and myeloid cells
    • Binds to B7 on APCs
    • Both PD-L1:PD-1 and PD-L1:B7 binding delivers an inhibitory signal to the immune cell
    • Fosters the development of Treg cells
    • Blocking this interaction is a major pharmaceutical target
18
Q

Immunoprivileged Sites

A
  • Classic anatomical sites protected from immune surveillance
    • CNS
    • anterior chamber of the eye
    • testis
    • placenta and fetus
  • Usually maintained behind a barrier
  • Barrier either:
    • inhibits the movement of immune cells into and out of the site
    • involves cell surface glycocalyx molecules that hide/cover tumor antigens
  • Acquired immunoprivileged sites
    • Healthy tissues may act as de facto privileged sites because they lack pro-inflammatory or ‘danger’ signals
19
Q

Passive Immunotherapy

A

Passive immunotherapy uses monoclonal antibodies (mAb) to tumor surface antigens.

  • Naked mAb
    • Rituximab (Rituxan) is a mouse/human chimeric mAb that binds CD20 on B-cell non-Hodgkin’s lymphoma
    • Herceptin is a humanized mAb that binds HER2/neu
    • Ipilimumb (Yervoy) is a fully human mAb that binds to CTLA-4
  • Conjugated mAbs
    • Used to target a drug, toxin, or radioactive substance directly to the cancer cells.
    • Allows the concentration of the drug to be high at the site of malignancy while sparing the rest of the body.
    • mAbs that recognize target tumors can be labeled with radionuclides that emit gamma rays or nanodots to detect tumors and metastatic disease
      *
20
Q

Therapeutic Vaccination

A
  • Vaccines given to patients who alrady have cancer in the hops of using Ag from the tumor to mobilize the immune response against the malignant cells
  • Technique involves:
    • Removal of dendritic cells from the patient
    • Pulsing the cells with tumor lysates or peptides
    • Reinfusing cells back into the patient
21
Q

Administration of Cytokines

A
  • Removed tumor cells
  • Transfected them with one or more cytokines
    • IFN-α, IFN-γ, TNF-α, IL-2, IL-12, GM-CSF
  • Returning the modified cells to the patient
  • Hopes of stimulating a targeted immune response against the tumor
22
Q

Preventative Vaccines

A
  • Vaccines that protect from known oncogenic viruses
  • Successful at decreasing the incidence of cancers
  • Decreases morbidity and mortality
  • Ex. HPV and Hep B vaccines
23
Q

CTLA-4 Pathway

A

Cytotoxic T lymphocyte antigen-4 (CTLA-4) / B7 Pathway

  • During normal T cell activation, TCR recognizes antigen bound to MHC II on an antigen presenting cell
    • Pathway requires a second signal often provided by CD28:B7.
    • Results in the activation and clonal proliferation of the T cell
  • After several days of proliferation, CTLA-4 (close member of CD28), is up-regulated on the surface of T-cells
    • CTLA-4 has a higher affinity for B7 than CD28
    • Interaction of CTLA-4 and B7 inhibits the activation response
    • CTLA-4 blocks T cells from attacking tumor cells
  • Ipilimumab is a mAb that targets CTLA-4
    • Disrupts its interaction with B7
    • Allows T-cells to attack tumor cells
24
Q

PD1 Pathway

(Programmed Cell Death-1)

A
  • Normally
    • PD-1 functions as an immune checkpoint
    • Role in preventing the activation of T-cells
    • Reduces autoimmunity and promotes self-tolerance
    • PD-1 is expressed on activated T cells, B cells, NK cells, and macrophages
    • Interacts with either PD-L1 or PD-L2
    • Tightly controlled through the microenvironment and cytokines
  • Some cancers overexpress PD-L1
    • Could promt CTL exhaustion
    • Down regulation of the immune response
    • Induction of Treg cells
    • Overexpression of PD-1 on tumor-infiltrating lymphocytes correlates with poor outcomes
  • New drugs target PD-1
    • Can activate the immune system to attack tumor cells
    • Ex. Opdivo
25
Q

Treg Inhibition

A
  • Selective Treg inhibitors
  • TGF-inhibiting mAb
  • Drugs are being explored to see if they can selectiely deplete Treg cells without impacting other T cell subclasses
  • Allows a more anti-tumor response
26
Q

Adoptive Cellular Therapy

A
  • The transfusion T-cells into a patient
  • Tested for treatment of cancer and chronic infections
  • In various stages of clinical trials
27
Q

Graft-vs-tumor / Leukemia

Adoptive Cellular Therapy

A
  • Treatment for certain relapsed or refractory leukemias
  • Includes infusion of alloreactive T cells following complete or partial hematopoietic stem cell transplant
  • Non-host T-cells attack non-donor targets including host tissue
    • Often cause graft-vs-host transplant reactions
  • Goal for alloreactive donor T-cells to respond against residual tumor cells
  • Contributes to eradication of the tumor or graft-vs-tumor response
28
Q

Chimeric Antigen Receptors

(CARs)

A
  • Engineered receptors in which a ligand binding domain in the form of a single polypeptide is grafted onto a T cell signaling domain
  • Chimeric molecule consists of:
    • antibody-derived recognition moiety
    • CD3-zeta (activation domain
    • costimulatory domain
  • CARs made in a lab and integrated into a retroviral vector
  • Patient T cells are harvested and transformed ex vivo
  • T cells transferred back into the patient
  • CAR T therapy currently used to treat acute lymphoblastic leukemia (ALL) by targeting CD19
    • Marker of both normal and neoplastic B cells
29
Q

Key Immune System Responsibilities

Preventing Cancers

A
  1. Suppresion of viral infections, which when unchecked can induce certain kinds of tumors
  2. Timely elimination of pathogens to reduce the extent and duration of inflammation, which can promote tumorigenesis.
  3. Immunosurveillence, which identifies and destroys transformed cells before they can establish malignancy.
30
Q

Malignant Cells

Mechanisms for Overcoming or Evading

Immune Responses

Summary

A
  • Selective pressures and genome instability promote decreased immunogenicity by
      • Antigenic modulation
      • Low levels of MHC class I expression
      • Decreased expression of adhesion molecules
      • Proteolytic shedding of MIC
      • Blocking antibodies
  • Tumor can arise in healthy tissues without a “danger signal”; therefore, their antigens are often viewed as self.
  • Tumors induce immune suppression
  • Tumors arise in immunoprivileged sites or sites with decreased immunosurveillance such as adipose tissue and the CNS

IMS: Immunology (19 decks)

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