Tumor Immunology

Question 1

What is a myeloma?

Answer 1

A cancer involving the bone marrow

Question 2

What are carcinogens?

Answer 2

Mutagenic agents that can cause increase in mutation rate (i.e., exposure to chemicals, radiation, and viruses)

Question 3

What is a tumor antigen? How are these targeted and eliminated by the immune system?

Answer 3

• Tumor antigen: mutated normal protein (via cancer) that is presented on MHC I
• Elimination via CD8 effector T cells with specificity for the new, mutant determinant

Question 4

What are 2 examples of tumor-associated antigens?

Answer 4

• Embryonic genes reactivated during post-natal life, and overexpressed: this protein will be a source of peptides loaded into MHC I in the tumor cell, and will be presented to naive T cells
  1. Because the embryonic genes weren’t expressed in during T cell devo and negative thymic selection, it is likely T cells will have specificity for the peptides
• Mutations that result in tumor formation may also cause increased expression of normal self protein by tumor cells -> increased density of normal self protein can sometimes be recognized by effector CTLs

Question 5

What is a tumor-associated antigen?

Answer 5

An un-mutated protein that is encoded on the germline DNA of a cell whose expression has been dramatically altered by a neoplastic event/process

Question 6

How did the mouse example from lecture illustrate the role of effector CTLs in the elimination of some tumors?

Answer 6

• Tumor cells transplanted to syngeneic and allogeneic inbred mice -> syngeneic succumbed to tumor and died, and allogeneic resulted in no tumor growth and survival
• Results indicate that effector CTL response directed at peptides presented in MHC I restricted fashion on tumor cells results in tumor killing -> CTLs almost certainly recognizing allogeneic peptides derived from mismatched MHC I on the two mouse strains (results would have been the same if CTLs had specificity for tumor antigen expressed by tumor)

Question 7

What is an oncogene? Provide some examples, and explain why these may be important in a host immune response to tumors.

Answer 7

• A mutated form of a proto-oncogene
• Proto-oncogene: a gene that, when mutated and activated, can transform a normal cell into a tumor cell
• Examples: HER-2, B-RAF, MYC, RAS, beta-catenin, VEGF
• Mutated forms of these genes can serve as unique tumor antigens because host’s T cell repertoire was generated (in most cases) before mutant form of protein available for presentation in (-) thymic selection -> most people are not tolerized against peptides derived from the mutant form of these host proteins

Question 8

What is a tumor suppressor gene? Proved some examples of these, and explain why they may be important in the host immune response to tumors.

Answer 8

• Gene that encodes proteins that exert control on cell growth rates (sometimes called anti-oncogenes)
• Examples: APC, TP53, Rb, CDKN2A, CDK4
• Mutated forms of these genes can serve as unique tumor antigens b/c host’s T cell repertoire generated (in most cases) before the mutant form of the protein was available for presentation during negative thymic selection. Most people not tolerized against peptides derived from mutant form of these host proteins

Question 9

In addition to oncogenes and tumor suppressor genes, what else might serve as a tumor antigen?

Answer 9

• Products of other mutated genes: genetic instability of tumor cells gives rise to many mutations of genes that have nothing to do with the transformation phenotype (i.e., cell division or its regulation)
  1. This is particularly common when tumor arose due to carcinogen or radiation exposure
  2. Mutated proteins are unique to tumor cells and can be CTL targets

Question 10

What are MAGE proteins, and how are they related to the host immune response to tumors?

Answer 10

• Melanoma antigen E (MAGE): family of proteins that are members of cancer/testis tumor antigen family
• Encoded on genes expressed in the testes, but normally not expressed in any other tissues
• B/c testes are immunoprivileged, MAGE proteins not available in T cell devo and thymic (-) selection -> most people not tolerized to them
• When MAGE expression upregulated in tumor cell, can serve as target for CTL responses -> also true for GAGE, BAGE, and RAGE family proteins
• Vaccines using MAGE, GAGE, BAGE, or RAGE proteins as immunogens currently in devo

Question 11

What are two examples of proteins abberantly, or overexpressed in tumor cells that can be tumor-associated antigens?

Answer 11

• HER2/neu: unmutated oncogene over-expressed on tumor cells of subset of human breast cancers
  1. Used as targets for tx w/monoclonal Ab drugs
• Oncofetal antigens: genes normally expressed only during embryonic development that are de-repressed
  in a tumor (tumor-associated antigens). Their protein products weren’t available during (-) selection of B and T cells, so possible to make a potent immune response to these proteins

Question 12

How are altered cell surface glycolipids and glycoproteins tumor antigens? Provide a specific example.

Answer 12

• Most tumors express elevated levels and/or abnormal forms of surface glycoproteins and glycolipids -> can be diagnostic markers/therapy targets (e.g., gangliosides, blood group antigens, and mucins)
• Several mucins of special interest and have been focus of dx and therapeutic studies
  1. CA-125, and CA-19-9 on ovarian carcinomas
  2. MUC-1 (breast carcinomas): tumor specific carb and peptide epitopes (induces Ab and T-cell/CTL response), making it a strong candidate for use in tumor vaccine

Question 13

What are cell-type specific differentiation antigens? Provide some examples.

Answer 13

• Molecules normally expressed by a cell at different stages of differentiation of that cell type
• Examples: CD20 (B cell lymphoma), T-lymphoblastic leukemia or T-all (CD1)
• B/c these are normally expressed proteins that were available during thymic selection, there should be no T cells recognizing determinants derived from these antigens -> NO tumor antigen-specific T cell responses
• These surface markers can be used as targets for dx or therapeutic Abs

Question 14

Name some viruses and their associated tumors. How can these tumors be prevented?

Answer 14

• Papillomavirus: warts (benign), uterine cervix carcinoma; worldwide
• Hep B: liver cancer; SE Asia, tropical Africa
• EBV: Burkitt lymphoma, B-cell lymphoproliferative disease, nasopharyngeal carcinoma; W Africa, Papua New Guinea, S. China, Greenland, immunosuppressed/deficient
• Human T-cell leukemia virus type 1 (HTLV-1): adult T-cell leukemia/lymphoma; Japan, West Indies
• HIV/HHV-8: Kaposi’s sarcoma; Central Africa
• These tumors can be prevented via vaccines to prevent infection, in some cases

Question 15

What are some of the strategies (5) that tumors use to evade immune responses?

Answer 15

• Antigenic drift: tumors genetically unstable, resulting in accumulation of mutations that allow them to evade pre-formed immune responses
• 1/3 to 1/2 of tumors have defects in expression of MHC I: allows them to evade CTL-mediated surveillance/killing, but makes them more of a target for NK cells
• Some tumors produce cytokines that down-regulate immune responses (e.g., TGF-beta)
• Some tumors express Fas-ligand on their surface, enabling them to induce apoptotic death of CTLs that interact closely with them
• Some tumors express PD-L1, a ligand for PD-1 (neg regulator protein) on effector T cells -> binding causes down-regulation of T cell effector function

Question 16

What are conjugated Abs, and how are they used in the treatment of cancer?

Answer 16

• MAb w/specificity for specific tumor Ag that have been conjugated to toxin, drug, or radionuclide designed to kill targeted tumor cells
• Those conjugated to radionuclides can be used to kill targeted tumor cell or diagnostically “find” location of tumors throughout the body

Question 17

What are some of the mechanisms of antagonist MAb drugs?

Answer 17

• Some bind to receptors, resulting in steric hindrance of ligand from binding
• Others bind the ligand, preventing it from binding its receptor (analogous to toxin or pathogen neutralization)
• Some bind important receptor and cause its depletion by endocytosis

Question 18

What are the 2 mechanisms of agonist MAb drugs?

Answer 18

• Bind a receptor and either mimic signaling through that receptor, or promote signaling through that receptor by recruiting ligand

Question 19

What is an example of how MAbs can be used as effectors of cell killing?

Answer 19

• Recruit host immunse cells (NK or CTL) to tumor cell, resulting in its destruction
• Example: recruitment of NK cells for ADCC (rutiximab anti-CD20 causes killing of B-cell lymphomas)
  1. If target of these drugs expressed at high enough density, activation of complement cascade can result in sufficient deposit of C3b and production of MAC for MAC-mediated destruction of these abberant host cells (does not usually occur in infection due to soluble and surface complement control proteins, but these can be overcome by high Ab binding w/these txs)

Question 20

What are Trastuzumab, Pertuzumab, and T-DM1?

Answer 20

• Antagonist antibodies that cause reduction in HER2 positive breast cancer tumor growth by preventing dimerization of HER2 and HER3 receptors
• T-DM1 unique b/c it combine MAb drug with chemo drug, making it a good drug for pre-treated HER2 positive breast cancers

Question 21

What are Cetuximab and Panitumumab?

Answer 21

MAb drugs that bind to EGFR, preventing it from being activated by EGF binding (antagonist Abs)

Question 22

What is CTLA-4? What is the MOA of MAb drugs with specificity for this marker?

Answer 22

• Important surface marker of Treg cells; when it binds to B7s, Tregs secrete TGF-beta, a powerful anti-inflammatory cytokine that can prevent naive T cell activation
• Also a surface marker of T cells that, when engaged with its ligand (B7.1 or B7.2), increases threshold of signaling required for activation of naive T cells, interfering with ability of CD28 on T cell to bind B7
• MAb drugs (i.e., Ipilimumab - melanoma tx) w/specificity for CTLA-4 are antagonists that prevent CTLA-4 from binding B7 -> prevents Tregs from performing their effector function, which is to prevent T cell activation on APC presenting Treg’s determinant
• NOTE: co-administration of anti-CTLA-4 and anti-PD-1 MAbs has shown very + results in human patients

Question 23

What is PD-L1, and how is it used in MAb tx?

Answer 23

• PD-L1: ligand that binds PD-1 on surface of effector T cells, interfering with their effector function; normally expressed on APCs in secondary lymph to help prevent CTLs from performing effector func there between time they are differentiating and leave to enter circulation
  1. PD-1: member of CD28/CTLA-4 protein family expressed on surface of effector T cells
• Tumor cells that express PD-L1 are protected from CTL-mediated killing
  1. MAb specific for either PD-1 or PD-L1 can prevent them from interacting, preventing tumor cell from down-regulating effector function of CTLs. Tx with these drugs causes rapid reduction in tumor size, although not yet known if pts treated w/these drugs live any longer -> early results promising
• NOTE: co-administration of anti-CTLA-4 and anti-PD-1 MAbs has shown very + results in human patients

Question 24

Explain the MOA of bispecific Abs.

Answer 24

• Recognize both CD3 and surface target of tumor cells, and recruit cytotoxic T cells to tumor cells
• Blinatumomab: single-chain bispecific Ab composed of anti-CD3 arm that recognizes T cell receptor and anti-CD19 arm that recognizes surface Ag found on B cell lymphomas
• Recruitment of T cells to tumor cells in this way results in efficient tumor cell killing, as if T cell had recognized its cognate peptide-MHC on tumor cell target

Question 25

What is chimeric antigen receptor (CAR)?

Answer 25

• Novel, personalized medicine approach to tumor therapy that depends on creation of chimeric CD8 T cells w/specificity__ determined by Ab specificity instead of T cell receptor specificity
• If unique tumor Ag can be ID’d on a pt’s tumor, MAbs
  specific for that determinant can be generated, then the rearranged heavy and light chain coding regions can be cloned from those cells and used to produce a synthetic
  gene that encodes a single chimeric chain that includes the CD3 zeta-chain
• T cells that have been genetically altered to express this construct can be generated, amplified, and infused into pt -> these CD8 T cells can now recognize unique tumor Ag using their chimeric surface Ab, and b/c CD3 zeta chain is part of construct, IC signaling occurs
• These CD8 T cells can be activated in secondary lymphoid tissues, and resulting CTLs can recognize tumor Ag via their chimeric surface Ab and be induced to degranulate on target cells bearing unique tumor Ag