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MB3008 > Cancer and the Immune System > Flashcards

Cancer and the Immune System Flashcards

1
Q

Predispositions of cancer

A
  • environmental and lifestyle (80%)
  • genetic (20%)
    • 2 to 8 sequential alterations
  • ~140 genes (Mut-driver genes) - mutations contribute to cancer
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2
Q

Driver mutation

A
  • change in gene that gives cancer cell a fundamental growth advantage for its neoplastic transformation
  • these genes function through a dozen signalling pathways that regulate
    • cell determination
    • cell survival
    • genome maintenance
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3
Q

Carcinoma

A
  • cancer drives from ectoderm or endoderm
  • colon cancer or breast cancer
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4
Q

Types of Cancer

A
  • leukaemia - cancer of blood or bone marrow - abnormal increase of immature WBCs
  • lymphoma - tumour in lymphoid tissue, bone marrow, lymph nodes
  • Solid Tumours
    • adenocarcinoma - colon, breast
  • melanoma - cancer of skin
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5
Q

Immune response to tumours

A
  • lymphoid cell infiltrates
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6
Q

Leukemia

A

Acute Lymphocytic Leukemia (ALL)

  • appearance and proliferation of immature, single, abnormal B cell
  • bone marrow, blood, liver, spleen, lymph nodes

Symptoms - anaemia, low WBC, weight loss, fatigue, malaise

  • absence of functioning granulocytes - prone to infections
  • thrombocytopenia
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7
Q

Treatment for decreased granulocytes

A
  • recombinant G-CSF and GM-CSF injections
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8
Q

Tumour Antigens

A
  • Tumour Associated Antigens (TAA)
    • antigens derived from normal cell but overexpressed in tumours
    • normal self proteins - minimally expressed by healthy tissue but constitutively over expressed in cancer cells
    • VEGF, HER2, hTERT, CEA, CD19
  • Tumour Specific Antigens (TSA)
    • antigens restricted to tumours - not found in healthy cells
    • result of malignant mutations or expression of viral antigens
    • neoantigens - created by mutations that change AAs
    • oncoviral antigens (HPV, HCV)
  • Oncofetal Antigens
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9
Q

Products of mutated genes

A
  • chromosomal translocations - leukaemias
  • point mutations (k-ras) - colon cancer
  • Neoantigens - protein antigens encoded by mutated household genes
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10
Q

Oncofetal antigens

A
  • these proteins are over expressed at high levels in some cancers
  • expressed during fetal development and not normal adult tissue
  • these protein antigens appear in development before immune system develops B and T cell tolerance to self proteins
    • if expressed later on cancer cells - recognised as non self - trigger immune response

e.g.

  • 𝛼-Fetoprotein - elevated in liver cancer
  • CEA (carcinoembryonic antigen) - adhesion protein - increased levels seen in colon cancer
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11
Q

Examples of oncogenic viruses

A
  • T-cell leukaemia (adult) - HTLV I
  • Burkitt’s lymphoma - EBV
  • Cervical cancer - HPV (16 & 18)
  • Liver cancer - Hep B & C
  • Nasopharyngeal cancer - EBV
  • Skin cancer - HPV
  • Stomach cancer - H.pylori
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12
Q

Immunity towards tumours

A
  • CD8+ CTLs - prinicipal mechanism of recognition of tumour cell antigens
  • NK cells - detects decreased MHC I - haemopoetic tumours
    • produce IFN-y, IL-2
  • Macrophages - presence correlates with tumour regression
    • produce TNF-a
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13
Q

Recognition of tumour cells

A
  1. ADCC
  2. CTL recognition of cancer peptides bound to MHC I on surface of cancer cell
  3. NK recognition of loss of MHC I on surface of cancer cell

*3 mechanisms results in apoptotic cell death and removal of apoptotic bodies via macrophages

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14
Q

Mechanisms of Tumour Evasion

A
  • lack of T cell recognition of tumour
  • inhibition of T cell activation
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15
Q

Anergy

A
  • immunologic tolerance characterised by the failure to mount a full immune response against tumour
  • failure of cancer cells to present cancer antigens due to downreg of MHC class I
  • failure of APC (DCs and macros) to present antigen to Th CD4 and CTL CD8
  • failure of CTL CD8 NK cells to engage and kill cancer cell by apoptosis
  • immunosuppressive environment of tumour
  • tumour editing - downreg of tumour markers

*new approaches needed to be design to wake up immune system

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16
Q

Ways of immunosuppression in TME

A
  • tumour microenvironment - crucial in coming up with treatments against solid tumours
  • tumours release adenosine under hypoxic conditions - suppress T cell activation - immunosuppressive environment
  • tumour cells secrete immunosuppressive cytokines
    • IL-10
    • TGFβ
17
Q

Therapeutic interventions for immunosuppressive TME

A
  1. Promote antigen presenting functions of DCs
  2. Promote production of protective T cell responses
  3. Overcoming immunosuppression in tumour bed
18
Q

Chemotherapy

A
  • combination of
    • prednisolone (decreases inflamm)
    • dexamethasone (decreases inflamm)
    • vincristine (prevents tubulin formation)
    • asparginase (breaks down asparagine - starve cancer cell - no growth)
19
Q

Biologicals

A
  • MAbs - to cancer specific antigens
  • Cytokines - IL2, IFNs
  • Immune checkpoint inhibitors - wake up immune system
    • DCs present antigens sufficiently
    • T cells kill tumour cells sufficiently
  • CAR-T cell therapy
  • Cancer vaccines - with or without DCs
  • post chemo
    • G-CSF and GM-CSF - increase WBC numbers
    • erythropoietin - increase RBCs
20
Q

MAb suitable for CD19 antigen

A
  • blinatumomab
    • single chain ab
    • specific for CD19 and CD3
    • targets CD19 and CD3 - recruits CTLs to kill ALL cells
21
Q

Immune Checkpoint Inhibitors

A
  • immune checkpoints - control immune response
    • downregulate immune response once infection under control
  • immune checkpoint receptors located on APC and T cell surface
    • dampen response by sending off signals to both cell typeS

Immunotherapy - immune checkpoint inhibitors

  • block the checkpoint proteins from binding with partner proteins
  • prevents the off signal being transmitted
  • T cells and APCs work functionally to kill cancer cells
22
Q

CAR-T Cell Therapy

A
  • combines abs and T cells
  • CARs - molecules genetically engineered into polyclonal T cell pop giving T cells the ability to recognise tumour-associated surface antigens
  • CAR in surface of T cell comprised of a single-chain variable fragment (scFv) - derived from mAb
    • connected to intracellular signalling domains - ensures T cell can be activated
  • combines specificity of ab with cytotoxic ability of T cell
  • involves the use of autologous T cells collected from cancer patient
23
Q

Allogenic CAR-T cells

A
  • Graft-versus-host disease (GVHD) - main barrier
    • CRISPR technologies may need to be involved to remove TCR and MHC genes in donor T cells
24
Q

CAR T cell challenges

A
  • success in haematological malignancies but limited success with solid tumours
  • challenges involved in targeting solid tumours
    • precise tumour antigen target required
    • overcoming immunosuppressive tumour microenvironment
  • Cytokine release syndrome (CRS)
    • immune effector cell -associated neurotoxicity syndrome (ICANS)
  • Need to develop off shelf CAR-T cells from allogenic donors
  • Cost (€320,000)
25
Q

Potential therapies to reduce CRS and ICANS associated with CAR-T cell therapy

A
  • infusion of mAbs - that will bind and neutralise cytokine effects
26
Q

Dendritic Cell Cancer Therapy

A
  • Sipuleucel-T - vaccine of enriched APCs/DC - pulsed with prostate acid phosphate (PAP) - reintroduced IV to induce immune response against prostate cancer
27
Q

Cancer Vaccination

A
  • prophylactic vaccines
    • HBV vaccine - against hepatocellular carcinoma (liver cancer)
    • HPV vaccine against cervical and head & neck cancer
  • vaccination of patients with their own cancer neoantigens
28
Q

Neoantigens

A
  • point mutations in genes that give rise to AA changes in proteins (non-synonymous point mutations) - generate neoantigens
  • effective anti-tumour immunity associated with T cell presence against neoantigens
    • MHC bound peptides that arise from tumour-specific mutations
  • neonantigens are immunogenic - not present in normal tissue
29
Q

Cancer Genome Sequencing

A
  • based on identification of neoantigens
  • tumour material analysed for nonsynonymous somatic mutations
    • sequencing of genomic DNA
    • Whole exon sequencing
    • RNA seq - identify mutations in expressed genes
  • in-silico analysis - see if predicted mutated peptides are likely to bind to MHC I and MHC II
  • synthesise these neoantigen peptides and inject them into cancer patient
30
Q

Types of Transplant

A
  • autograft - one part of body to another (same person)
  • isograft - between genetically identical individuals (monozygotic twins)
  • allograft - between different members of same species (different person)
  • xenograft - between members of different species (pig and human)
31
Q

Types of rejection reactions

A
  • hyperacute - mins/hours - preformed anti donor , abs and complement
    • blood groups
  • accelerated - days - reactivation of sensitised T cells
    • 2nd graft
  • acute - days/wks - primary activation of T cells
    • 1st graft
  • chronic - months/yrs - cause is unclear (abs, immune complexes)
    • genetic disparity between donor and recipient
32
Q

Primary difference between one persons individuals cells and another persons

A
  • AA sequence for MHC I and II
  • each individual has their own unique MHC/HLA genes giving rise to different MHC/HCLA class I and II proteins - haplotype
  • MHC proteins are co-dominantly expressed
    • 2 x each 6
    • HLA, A, B, C, DR, DP, DQ
  • one MHC haplotype inherited from each parent
33
Q

Why is efficient matching of donor and recipients MHC crucial?

A
  • antigens from donor or graft - picked up by recipient DCs
  • presented as foreign antigen to CTLs and THs in lymph nodes
  • graft MHC I and II - importnat for foreign recognition
34
Q

Therapies to prevent organ rejection

A
  • most immunosuppressive therapies target production or inhibition of IL-2
  • Cyclosporin - replaced by …
  • Tacromilus
  • Basiliximab - mAb (IL-2r blocker)
  • Mycophenolate - inhibits B & T cell proliferation - reversibly inhibits inosine monophosphate dehydrogenase - inhibits purine biosynthesis pathway
  • steroids no longer used
35
Q

How can the immune system be immunosuppressed to inhibit organ rejection?

A
  • IL-2 gene
    • IL-2 production - T cell activation and immune activation
    • IL-2 stimulates many parts of immune response
  • produced by CD4+ Th

Inhibited by cyclosporin and tacroplimus

36
Q

NFAT

A
  • essential for IL-2 transcription
37
Q

Cyclosporin mechanism

A
  • used to prevent organ/graft rejection
  • blocks activity of a specific phosphatase - calcineurin
  • calcineurin - unable to remove phosphate group from NFAT
  • NFAT remains active in cytoplasm
  • No IL-2 production
  • No Th cell activation - immunosuppression
38
Q

Where does NFAT bind?

A
  • promoter region of IL-2 gene
39
Q

Inhibitor of Calcinuerin

A
  • FK506
  • Takrolimus - from bacterium strep tsukubaensis

MB3008 (9 decks)

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