Module 10 Cancer and Immunology Flashcards
Tumor
Neoplasm
Differences between benign tumor and malignant tumors
Benign tumors are encapsulated, localized and limited in size
Malignant tumors, continually increase their size by breaking through basal laminae and invading adjacent tissues
Different types of cancers
- Cancers of epithelial cells are carcinomas
- Cancers of other cell types are sarcomas.
- Cancers of circulating immune system cells are leukemias.
- Solid lymphoid tumors are lymphomas.
What gives rises to cancer
Cancer arises from a cell that has accumulated multiple independent mutations in several genes determining cell division, proliferation and survival.
Proto-oncogenes
Genes that contribute to the normal processes of cell division that occur every day in some cells of the human body. There are more than 100 human proto-oncogenes. They encode growth factors and their receptors as well as enzymes that transduce signals from the receptors to the nucleus there by initiating gene transcription.
Mutant Proto-oncogenes that contribute to malignant transformation are called oncogenes.
Tumor suppressor genes
Such as a group of genes encoding p53, protein made by cells with damaged DNA, which induces them to die by apoptosis. Loss of p53 gene or substitutions that compromise its protective function are the most abundant mutations in human tumors. >50% of cancers have mutant p53
How many independent mutations a human cell must accumulate before it becomes cancerous?
At least 5 or 6 independent mutations. The precise number depends on the cell type and the particular genes that mutate.
All human cancers arise from a single cell that underwent malignant transformation.
Li-Fraumeni syndrome
Or genetic condition that predisposes to various cancers that arises at an unusually young age
Characterizing the Syndrome is inheritance of an inactive allele of a tumor suppressor gene such as P 53
Carcinogens
Agents that increases the mutation rate in human cells
Oncogenic viruses
Viruses that transform a human cells and can cause cancer. They typically produce chronic infections and diseases.
What are the seven characteristics that all cancer-causing cells share?
Cancer neoantigens / neoantigens
Peptides presented by MHC1 have amino acid substitutions not encoded in the patient’s germ line and to which the patient is not tolerant.
These peptide antigens recognized by T cells, in complexes with the HLA I, are called neoantigens or cancer neoantigens
T cell exhaustion
When cancer progresses to the point at which tumors are detectable and disseminating, the cytotoxic T cell response can no longer control the proliferating tumor cells. In losing the battle, the CD8 T cells become dysfunctional — a state called T-cell exhaustion that is brought on by the persistence of antigen and inflammation.
Features of T cell exhaustion
- Progressive loss of effector functions, a distinctive pattern of gene transcription
- Expression of several inhibitory receptors
- Metabolic change from glycolysis to oxidative phosphorylation
- Exhausted T cells are phenotypically different from aneroid, memory, effector, or naive T cells.
What tumors are more immunogenic than others?
Cells transformed by oncogenic viruses give rise to the most genetically and antigenically distinctive tumors
Less immunogenic are tumors arising from a transform to cell that has point mutations in a half dozen oncogenes and tumor suppressor genes. As the tumor grows further mutations occur, introducing genetic heterogeneity into the tumor cell population. Selection for Darren cells with faster growth or increased metastatic potential causes the genomes of the tumor to diverge even further from that of the human host.
Tumor specific antigens
Presenter only on tumor cells and are also called neoantigens
Tumor antigens: antigens to which T cells respond are called tumor antigens
Tumor associated antigens
Present on tumor cells, and also on some types of normal cells often at relatively low level
Derived from normal human proteins, to which the immune system has either not being exposed or not become tolerant. Do you include proteins that are normally present in human logically privilege of size of the body, such as the eye, or present in trace amount that T cells cannot detect
Cancer / testis antigens are a prominent class of tumor-associated antigen
Cancer stem cells
Self-renewing and more resistant to toxins and radiation used to treat cancer
How does immune response imposes tumor section on tumor cell population
- Immune responses cause the selection for tumor cells that have reduced expression of tumor antigens, or for tumor antigens with mutated epitopes that are not recognized by the existing effector T cells or antibodies
One example is the the process of epithelial cell transformation
How does CD8 T cell responses select variant cancer cells
CD8 T cells are the most powerful effector cell for tumor control. It recognizes the complex of a tumor-specific peptide and an HLA class I allotype on tumor cell surface and responds by killing the tumor, which selects for variant tumor cells that have lost or decreased expression of one or more HLA class I allotypes
Some 30-50% of all human tumors have reduced expression for one or more of HLA I calls allotypes. Tumors that lose expression of beta2-microglobulin, the conserved polypeptide of HLA class I, are particularly successful
Loss of HLA class I expression makes tumor cells resistant to T cell attach but susceptible to NK cell attack
The cells lack HLA class I are recognized as non-self by NK cells
What is immunosuppressive tumor micro-environment
In the absence of inflammation, tumor cell antigens are processed and presented to T cells by dendritic cells that lack B7. The lack of co-stimulation by B7 anergizes the tumor-specific T cells.
Immunosuppressive cytokines unregulated in tumor cells: TGF-beta, IL-10 and recruitment of T reg cells.
Burkitt’s Lymphoma
- Derives from a germinal center B cells
- Mutation: translocation between the MYC proto-oncogene on chromosome 8 and an immunoglobulin locus
Hodgkin’s lymphoma
- Derives from germinal center B cells
- Mutations: lack of Pax-5 & expression of Cd30 and CD15
Pax-5 is the defining transcription factor of the B-cell lineage. As a consequence, the tumor lacks B-cell signaling pathways, including signals that would have come from the BCL
Anaplastic large-cell lymphoma (ALCL) is a T-cell lymphoma distinguished by large horseshoe-shaped cells
Mutation: translocation between the anaplastic lymphoma kinase (ALK) gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5
How does naked antibodies kill tumor cells?
Naked antibodies, reduce tumor growth by inhibiting the functions of signaling receptors, and promoting the opsonization of tumor cells and their phagocytosis or killing by NK cells
MoA of most mAb depends on NK cell-mediated antibody-dependent cell-mediated
cytotoxicity (ADCC).
One an unwanted feature of ADCC is that activation of the NK cell is followed by shedding of FcrRIII from the NK cell surface the rough the action of the ADAM33. Adding an inhibitor to ADAM33 to the patients treatment increases tumor-cell killing by ADCC
VEGF
Vascular endothelial growth factor. By neutralizing VEGF if prevents the angiogenesis that is necessary for tumors to grow
Checkpoint Inhibitors
CAR-T
