Immune Response To Tumor 6u693k

IMMUNE RESPONSE TO TUMOR Dr. Elyusrar A. Jalal Ph. D

CANCER : UNCONTROLLED GROWTH OF TRANSFORMED CELLS Single transformed malignant cell

Tumor mass metastasis

Clone of transformed malignant cells

TUMOR REJECTION ANTIGENS RECOGNIZED BY THE IMMUNE SYSTEM 1. Point mutation in self protein during the process of oncogenesis 2. Cancer-testis antigens. Protein encoded by genes that are normally expressed only in male germ cells in the testis. Male germ cells do not express MHC molecules.

3. “Differentiation antigens”, protein encoded by gens that expressed only in particular type of tissue. 4. Antigens that overexpressed in tumor cells compared with normal cells 5. Molecules that display abnormal post-translational modifications 6. Abnormal post-transcriptional modifications. Proteins that are generated when one or more introns are retained in the mRNA 7. Proteins encoded by viral oncogens

TUMOR REJECTION ANTIGENS (TRA) Peptides of tumor-cell proteins that are presented to T-cell by MHC molecules These peptides become the target of a tumor-specific T-cell response

Tumor rejection antigens may arise by point mutations in self proteins, which occur during the process of oncogenesis. Can be recognized by mature T cells

Tumor cells downregulate MHC class I expression

IMMUNE SYSTEM INTERACTION WITH TUMOR

ELIMINATION OF TUMOR IMMUNOSURVEILANCE

IMMUNOTHERAPY

Using the immune response to attact tumor

CONTROL TUMOR GROWTH USING MONOCLONAL ANTIBODY AGAINST TUMOR ANTIGENS •

Requires that a tumor specific antigen be expressed on the tumor cell surface

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NK cells, ADCC (antibodydependent cell-mediated cytotoxicity)

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Antibody / fragmen of antibody conyugated to toxin

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Antibody conjugated to radioactive substance

• Linking the antibody to a toxin (immunotoxin). The antibody must be internalized to allow the cleavage of the toxin in the endocytic compartment, allowing the toxin to penetrate and kill the cell • Conyugated to chemotherapeutic drugs (adriamycin) or radioisotopes • These have the advantage of also killing the neighboring tumor cells

ENHANCING THE IMMUNE RESPONSE TO TUMORS Vaccination:

1. Vaccine against human papiloma virus was 100% effective in preventing cervical cancer 2. Vaccines based on tumor antigens. Ideal approach to T-cell mediated immunotherapy, but difficult to develop. Relevant peptide of tumor rejection antigens may not be shared between different patients’ tumor 3. Cell-based vaccines, prepared by mixing tumor cells or tumor extract with adjuvants 4. Whole protein or peptide vaccines of identified tumor rejection antigen, istered alone or presented by patient’s own dendritic cells 5. Vaccination based on isolation of heat-shock proteins from tumor cells. Dendritic cells express receptors that mediate the uptake of certain heat-shock proteins and can deliver the peptide into the antigen-processing pathways for presentation by MHC class I molecules. The effectiveness is limited