TUMOR IMMUNOLOGY

Cancer The proliferation of normal cells is carefully regulated. However, such cells

when exposed to chemical carcinogens, irradiation and certain viruses may undergo mutations leading to their transformation into cells that are capable of uncontrolled growth, producing a tumor or neoplasm.

Benign: if it is not capable of indefinite growth and the host survives, which are self-limited, and do not invade or metastasize.

Malignant if the tumor continues to grow indefinitely, metastasizes (spread to other locations in the body via lymph or blood), eventually killing the host.

Most cancers form a tumor but some, like leukemia, do not. Cancer causes about 13% of all human deaths. Cancers can affect all animals.

Oncology. The branch of medicine concerned with the study, diagnosis, treatment,

and prevention of cancer.

.

Classification Carcinoma: Malignant tumors derived from epithelial cells. This group

represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.

Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.

Lymphoma and leukemia: Malignancies derived from hematopoietic cells.

Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).

Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.

Experimental Evidence for Tumor Antigens and Immunr Response

1. Inject Tumor 2. Excise tumor 3. Re-challenge withsame tumor

4. No tumorgrowth

1. Inject Tumor 2. Excise tumor 3. Re-challenge withdifferent tumor

4. Tumorgrows

Dendritic cell and tumor immunity

9

Indoleamine2,3-dioxygenase(IDO)

10

Biochemical properties of IDO• IDO is a monomeric protein containing heme and encoded by a gene

over 15 kbp of DNA located on the short arm of chromosome 8 in humans and mice (Mellor AL et al., 2004).

• The indoleamine 2,3-dioxygenase-like protein (INDOL1 or IDO2) gene was recently identified and found to locate adjacent to the IDO gene in mice and human (Ball HJ et al., 2007).

• The signaling of IDO activation occurs mainly through (JAK-STAT) and (NF-κB) pathway (Mellor AL et al., 2004).

• IDO might bridge between DCs and Tregs (Puccetti P et al., 2007).

11

Kynurenine Pathway

12

Fate of Tryptophan

General protein

synthesis

Serotonin biosynthesis

Catabolism through the kynurenine

pathway

13

14

IDO Molecular genetics and enzyme activity

IDO transcription act through JAK–STAT signaling pathways on INF stimulatory response elements (ISREs) and γ-activating sequences (GAS) in the IDO promoter.

Transcriptional repressor of IDO are not defined, cis and perhaps trans-regulatory factors are inferred.

No specific post-translational modifications of IDO have yet been identified . Functional activity might also be regulated at the level of holoenzyme assembly (that is, incorporation of the haeme prosthetic group).

15

Essential amino acid deficiency antagonizes signalling through the mTOR (mammalian target of rapamycin) kinase pathway. mTOR signalling is required for normal initiation of ribosomal translation. This pathway is important for growth-factor signalling, and T cells are particularly sensitive to inhibitors of mTOR, such as the immunosuppressant drug rapamycin. A second amino-acid responsive pathway is initiated by the GCN2 kinase, which contains a binding domain that is specific for the uncharged form of transfer RNA (tRNA). Precisely how activating this stress-response pathway or inhibiting the mTOR pathway might affect the programme of T-cell activation is currently unknown.

16

17

Interactions between the tumour and cells of the immune system that foster an immunosuppressive microenvironment.

18

19

Andrew L. Mellor and David H. Munn.

Before1998

• IDO was thought to participate in innate host defence against pathogens.

After1998

• They proposed that IDO also has a role in immune regulation, as inhibiting IDO during pregnancy in mice allowed maternal T cells to attack allogeneic fetal tissues.

2004• Many studies had identified IDO as a

component of the inflammatory response associated with infection, cancer and autoimmune and allergic diseases.

20

Inhibition of indoleamine 2,3‑dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.

(Muller, A. J et.al.2005) Nature Med. 11, 312–319

Three key questions were unresolved

The role of IDO in immune regulation and

the therapeutic potential of

manipulating IDO activity?

The origin and biological signifi cance of ‘IDO-

competent DCs?

The molecular mechanisms that

explained IDO-mediated regulation of immunity?

21

Substantial progress on all three issues has been made in the last 7 years.

IDO has been shown to control local innate immunity (inflammation) and to regulate antigen-specific adaptive immune responses in settings as diverse as mucosal tolerance, asthma, acquired tolerance to allograft, chronic infection and tumour-induced immunosuppression.

In the case of cancer, IDO expression reported in patients with malignancy. Treating tumour-bearing mice with IDO inhibitors enhances tumour-specific immunity and synergizes with cytotoxic chemo therapy to improve treatment of established tumours (Munn et. al 2011), and IDO inhibitors have recently entered Phase II oncology trials.

• IDO expression is also a common feature of auto immune, allergic and graft-versus-host dis eases, and in these settings IDO inhibition markedly

exacerbates disease severity.

22

Infectious disease Transplantation

IDO inhibits pathogen replication appears to apply in some settings. In other settings, pathogen-induced IDO may attenuate host T cell immune responses and facilitate the persistence of certain infections, such as HIV and tuberculosis (Favre, D. et al.2010),(Desvignes, L.et al. 2009) Thus, depending on the pathogen, IDO may help or hinder antimicrobial immune responses, and this is an active area of research.

David Wilkes and colleagues first showed that IDO gene transfer protected lung allografts, pancreatic islet, skin and corneal allografts. Of note, overexpression of IDO in transplanted lungs profoundly impairs the cytotoxic functions of host T cells that infiltrate the allografts (Liu, H. et al.2009). IDO helps to establish acquired immunological unresponsiveness at sites of inflammation.