tumor immunity Flashcards
characteristics of cancer cells
- stimulate their own growth
- ignore growth-inhibiting signals
- evade apoptosis
- develop a blood supply: angiogenesis
- metastasis
- replicate continuously
- evade immune response
define tumor
(neoplasm)- cells growing abnormally
define metastasis
spreading of cancer cells to distant sites, focus of new growth
define malignant transformation
the process through which a cell becomes able to form cancer
- this involves accumulation of multiple mutations in genes that regulate cell division and cell survival
difference between benign & malignant
benign- adenoma
- contained by fibrous connective tissue
- localized and limited in size
malignant- adenocarcinoma
- not limited by capsule, invasive, can break through basal laminae & invade adjacent tissues
common sites for tumor development
- sites of lots of cellular turniver
- bone marrow, lymph glands, lungs, reproductive organs
causes of cancer
1- environmental- often referred to as mutagens, carcinogens, oncogenic viruses
2- genetic- mutations in certain genes
. BRCA1/BRCA2- mutant forms of these tumor suppressor genes increase risk of breast and ovarian cancer by five fold (60% compared to normal 12%)
genes whose product positively regulate cell division & function normally in normal cells
proto-oncogenes
mutated versions of proto-oncogenes that contribute to malignant transformation
oncogenes
encode proteins that prevent unwanted proliferation of mutant cells
tumor suppressor genes
tumor suppressor gene- over 50% of of human tumors have a mutation in this gene
p53
many human tumors are caused by viruses
1- DNA viruses:
. Papillomavirus- warts (benign), carcinoma uterus
. Hepatitis B virus- liver cancer
. Epstein-barr virus- Burkitt’s lymphoma
2- RNA viruses:
. HTLV-1- adult T-cell leukemia/lymphoma
name 3 cancers of the immune system
1- leukemia- cancer of immune system cells
2- lymphoma- involving solid lymphoid tumors
3- myeloma- involving bone marrow
how can the immune system recognize tumors as dangerous and target them for removal?
- tumor antigens
- cells that are malignantly transformed have genotypic differences that distinguish them from healthy cells
- antigens present on tumors cells, but not normal cells are called tumor-specific antigens
- antigens present on tumors but also normal cells ( at lower expression levels) are called tumor associated antigens
describe tumor specific antigens
- present on tumor cells but not on normal cells (certain p53, ras, and B-catenin variants)
- products of oncogenic viruses (EBV and HPV)
describe tumor associated antigens
- not necessarily unique to tumors
- overexpressed by tumors: Her2-Neu
- tumor-specific post-translational modificications, Muc-1 abnormal glycosylation and localization
describe cancer/testis antigens
tumor associated antigens
- expression restricted to gametogenic tissues (immunologically privileged) and cancer
- genes frequently map to chromosome X (50%)
- immunogenic in cancer patients
- expression may be related to tumor progression and with tumors of high metastatic potential
describe tumors and their immunogenic-ness
tumors may not be very immunogenic
- chemical or radiation-induced tumors as well as virally-induced tumors are generally immunogenic b/c of the generation of altered self
- however, many spontaneous tumors may not be very immunogenic
- an immune response against a self-antigen generally requires breaking self-tolerance
describe immune evasion by tumors (best & worst case scenarios)
best-case scenario: tumor cell- has tumor specific antigens that can be recognized by MHC—> activation of T cell response
bad: tumor cell may not express tumor specific antigens, or MHC class I or they may express inhibitory ligands and immunosuppressive cytokines—> inhibition of T cell activation
mechanisms of tumor-mediated immune suppression
secreted factors: IL-10, TGF-B, PGE-2 (all decrease the potency of anti-tumor effector cells)
- tumors can provide negative costimulation:
CTLA-4/B-7 inteactions
PD-1/PDL1 interactions
downregulation of MHC
TGF-B positively regulates ___
Treg cells —> immunosuppressant
more mechanisms of tumor-mediated immune suppression
- T regulatory cells
- CD4+ and CD25low and/or Foxp3-Tregs
- suppressive activity mediated through secreted factors IL-10 and TGF-B
- in vivo depletion of Tregs through anti-CD25 treatment slowed the growth of transplantable tumors in syngeneic mice
mechanisms of tumor defense
- innate immunity- Nk cells, macrophages, DC’s
- adaptive immunity- CD4+ and CD8+ T cells, more limited role for B cells
NK cells and cancer
- mice lacking NK cells have faster growing tumors
- tumor cells that lack MHC molecules are sensitive to NK-mediated killing
- tumors can express ligands that activate NK-mediated killing
- NK cells express IFN-y and TNF-a which can inhibit tumor growth
opportunities for immunotherapy
often, primary tumors are not eliminated by immune therapy alone
- after surgery and radiation, opportunities to fight metastases or silent tumors with immune therapy
- need to wait for restoration of immune system following certain chemo therapies
cell-based immunotherapy for tumors, cell transfer
tumor-bearing patient- isolate lymphocytes from blood or tumor infiltrate
- expand in culture with IL-2 may be transfected with CAR gene
- transfer back into patient –> tumor regression
monoclonal antibody therapy
monoclonal antibody directed against certain antigens expressed by tumor cells
- ex: CD20 antibody can be linked to a toxin, antibody homes to tumor and delivers toxin, leads to its destruction
