1. Cancer and the Immune System
Immunology

2. Cancer is altered self cells that have escaped normal growth regulating mechanisms.
These cells give rise to clones of cells that can expand to a considerable size, producing a tumor, or neoplasm.
If it does not invade the healthy surrounding tissue it is called benign.
A tumor that continues to grow and becomes progressively invasive is malignant

3. Malignant transformation of cells: Transformation: is alteration of cell morphology & growth properties. The changes in properties are:- 1.     ↓ requirement for growth factor. 2.      No longer anchorage-dependent. 3.      They grow in a density-independent fashion. 4.      They can subculture indefinitely (immortal).

4. Mutation of cells caused by various physical agents (UV light & ionizing irradiation). Chemical  agents ( alkylating agents). These will induce transformation with 2 phases, which are: A.    Initiation, which involve change in the genome but, does not in itself lead to malignant transformation. B.     Promotion by promoters that stimulate cell division & lead to malignant transformation.

5. These chemical & physical Ag that induce tu are called carcinogen, of which, if it induces 2 separate tu at different sites in the same patient → the tu Ag are distinct, so, the immune response to one tu does not protect against other tu. I.e. they were highly specific. In contrast, in virally induced tu , the tu express tu Ag that, were shared by all tu induced by the same virus, even if in different site, i.e. there is cross-reaction, while, tu cell induced by different viruses do not cross-react. Tumor of immune system: Classified into: 1. Lymphoma which, tend to proliferate as solid tu. 2. Leukemia which, tend to proliferate as single cell.

6. Oncogenes and Cancer Induction Most, if not all, oncogenes (both viral and cellular) are derived from cellular genes that encode various growth-controlling proteins. Oncogenes and tumor suppressor genes have been shown to play an important role in cancerous process, by regulating either cellular proliferation or cell death.

8. Cancer-associated genes can be divided into three categories that reflect these different activities. 1. Induction of cellular proliferation. By proteins that, function as growth factors or growth factor receptors. Also proteins that function in signal-transduction pathways or as transcription factors. 2. Inhibition of cell proliferation by proteins called tumor suppressor genes, or anti- oncogenes. Inactivation of these results in unregulated proliferation. For e.g. p53 which is nuclear phosphoprotein that inhibits formation of small-cell lung cancer and colon cancers. 3. Regulation of programmed cell death as bcl-2 which is suppressor of apoptosis.

11. Tu associated Ag: 2 types were detected which are:
  Tu specific transformation Ag (TSTA), which, is unique to tu cell & not found in normal cell.
  Tu associated transplantation Ag (TATA), which is not unique to tu but, may be protein that expressed on normal cell  also, which are:
1.   Oncofetal Ag as, * Alpha-fetoprotein (AFP), that is normally present only during fetal life so, if it ↑ in adult life, it indicate liver cancer                        
 * Carcinoembryonic Ag (CEA) which, if ↑ in adult so, indicate colorectal carcinoma.
2. Over expression of normal Ag, as growth factor & growth factor receptor.

14. The tumor Ag recognized by human T cells fall into one of four major categories: ■ Ag encoded by genes exclusively expressed by tumors. ■ Ag encoded by variant forms of normal genes that have been altered by mutation. ■ Ag normally expressed only at certain stages. ■ Ag that are over expressed in particular tumors.

15. Mechanisms of tu immunity:
Tu can induce potent immune responses as:
1.     It induce both humoral & CMI with, CMI plays a major role of which; it will attack Tu cells & limit their proliferation. Some tu cell can escape from immune response by modulation.
Tu Ag induce tu specific CTLs that, recognize tu Ag presented by class I MHC on tu cell (but, there is ↓ in expression of class I MHC in a number of tu so, it will limit the role of CTL in their destruction).
2.      Killer cell & macrophage are important in tu recognition, in which, both recognize tu with MHC independence. So it recognize tu even if, ↓ in MHC is present. As well, both cells have FC receptor that can bind to Ab coated tu cell leading to ADCC.
3.      NK cells, which act without Ab.
4.     Tu Ag can stimulate the development of specific Ab, of which some of them are cytotoxic, but others, called blocking Ab, enhance tu growth by blocking recognition of tu Ag by the host.

16. 5. The Role of Cytokines
IFN-γ. This cytokine can exert direct anti-tumor effects on transformed cells enhanced class I MHC expression targets for CD8+ T cell recognition and destruction
IL-12 driving the development to T-cell pathways: this cytokine encourages DCs to activate strong TH1 and CTL responses (enhance anti-tumor immunity)
TNF-α was named for its anticancer activity. When it was injected into tumor-bearing animals, it induced hemorrhage and necrosis of the tumor.

17. Tu evasion of the immune system:
1.     Anti-tu Ab can enhance tu growth because it act as blocking factor.
2.     Ab can modulate tu Ag. This is called Agic modulation.
3.     Tu cell frequently express low level or even complete loss of class I MHC & that will accompany progressive tu growth. So absence of class I MHC in tu cell indicate poor prognosis.
4.     Tu cell may provide poor co-stimulatory signals, so poor immunogenicity of tu.
5. Tu cell that decreased expression of ligands that bind activating receptors on NK cells allows these cells to avoid NK cell-mediated killing.
6. The up-regulation of anti-apoptotic mediators and the expression of mutated or absent death receptors can lead to tumors that are resistant to programmed cell death signals.

19. Cancer immunotherapy:
Approach of treatment is to augment natural defense mechanisms by:
Manipulation of co-stimulatory signal through providing signal necessary for activation of CTL precursor.
Enhancement of APC activity as for e.g. culture of dendritic cell (from peripheral blood ) in the presence of GM-CSF, TNF-α & IL-4. All these 3 cytokines induce the generation of large number of dendritic cell.

20.  Cytokines therapy as,
A.  IFN will ↑ class I MHC.
B.   TNF- α & β which, have direct anti tu activity
C.   IL-2: (in high concentration) will activate one type of NK cell called LAK cell( lymphocyte activated killer cell), which are activated NK cell with TCR  that kill tu cell & not normal cell.
So,  Lymphocyte + IL-2 → LAK → tu cell destruction.
Also the tu contain specific lymphocyte that have been infiltrated the tu & have antitu response. These are called TILs (tu-infiltrating lymphocyte).
As well, IL-1, 2, 4, 5, 12. GM-CSF. All augment immune response against tu. But the difficulty is that all have S.E

21.      Monoclonal Ab as:
1.     Anti growth factor receptor e.g, anti HER-2 for breast cancer.
2.     Anti to tu specific Ag, that is coupled with radio-isotopes, which is called guided missile therapy.
3.     Also the use of what is called immunotoxin (diphtheria toxin ).
4.     BCG vaccine used to boost tu immunity by activating macrophage & ↑   the expression of various cytokine.

22. Tu vaccine:
aim is to focus the cellular arm of immune system against the tu – associated Ag that, exist in the body. So if immune system recognizes this Ag, it will act against it. 
So tu Ag + cell contain MHC I (dendritic cell) → Hybrid → immunogen.
The advantage of this is that, the hybrid cell has the Ag presenting capability of a dendritic cell but, also contains the Ag from the patient’s tu cell, then dendritic cell process tu Ag & present it to immune system of the patient.