Cancer and the immune system

1. Cancer and the immune system Lecture 1 Thursday, January 18, 2007 Refs. Kuby Immunology Chapter 21 Basic Pathology 201-205

2. Review of neoplasia terms • Neoplasm--group of cells that no longer respond to normal growth-control mechanisms • May be benign or malignant. • Cancer = a malignant neoplasm • Characteristics are invasion and/or metastasis. • Immunologically, cancer cells are altered self cells.

3. Classification of cancer • Carcinomas originate from endodermal or ectodermal tissues; >80% of cancers • Hematopoietic malignancies; ~9% of cases • Leukemia: tumor proliferates as individual cells • Lymphoma: cells form solid masses • Sarcomas originate from mesodermal connective tissue; ~1% of cases

4. Transformation • Normal cultured cells treated with carcinogens or certain viruses have alterations in morphology and growth requirements. • When injected into animals, transformed cells produce tumors. • Transformed cells have cancer-like properties. • Both cancer and transformed cells can be subcultured indefinitely. • Inducing agents--chemicals, viruses, UV irradiation • 2 phases: initiation and promotion • Initiation involves heritable change to genome of cell • Promotion involves stimulation of cell division leads to malignant transformation.

5. Viruses that induce cancer • DNA viruses • polyoma and SV40 • Human papilloma virus is implicated in over 99% of cervical cancers. • Hepatitis B virus associated with liver carcinoma • Epstein-Barr virus is associated with Burkitt’s lymphoma in Africa and nasopharyngeal carcinoma in Asians. • RNA-retroviruses integrate into host genome • Human T-cell Leukemia virus (HTLV-1) • HIV-1 positive patients have a high incidence of Kaposi’s sarcoma associated with human herpesvirus-8.

6. Oncogenes • Some retroviruses contain oncogenes (v-onc) • Rous sarcoma virus v-src • avian leukosis virus • Normal cells have sequences homologous to viral oncogenes call cellular oncogenes or proto-oncogenes • c-src is homologous to v-src • Most oncogenes encode proteins that control cell growth.

7. Groups of genes associated with development of cancer • I Genes that induce proliferation • Growth factors, receptors for growth factors, transcription factors • II Genes that inhibit proliferation • Tumor suppressor genes--RB, p53, etc. • III Genes that regulate programmed cell death • bcl-2 suppresses apoptosis See table 21-1 for organized list of genes and their functions

8. Role of DNA repair enzymes • Xeroderma pigmentosum-a defect in a gene that encodes DNA repair enzyme. • Cannot repair UV-induced mutations. • High incidence of skin cancer.

9. Induction of cancer is a multistep process • Steps are well worked out for heritable colon cancer (familial adenomatous polyposis) KI fig. 21-4

10. Immune surveillance hypothesis • Early 1900s Paul Ehrlich-cancer is frequent but usually eliminated by immune system. • 1950s Lewis--purpose of CM immunity • Evidence for immune surveillance: • Increased cancer in transplant patients taking immunosuppressive drugs appears to support hypothesis. • But no increased cancer in nude mice. Nude mice lack thymus and thus T cells. • Increased cancers were mainly of immune system • Immune surveillance hypothesis remains unproved.

11. Tumors of the immune system • Leukemia-- proliferation as individual cells • detected by increased number of cells in blood • Lymphoma (lymphosarcoma)-- solid tumor • ALL - acute lymphocytic leukemia • AML - acute myelogenous leukemia • CLL - chronic lymphocytic leukemia • CML - chronic myelogenous leukemia • Acute forms arise in less mature cells. • Good prognosis; permanent remission • Treatment success for all leukemias has greatly increased.

12. Burkitt’s Lymphoma • A neoplasm of B lymphocytes • Translocations induce c-myc transcription • 75% c-myc from 8 to 14 (Ab heavy chain) • 9% kappa from 2 to 8 • 16% lambda from 22 to 8 • Epstein-Barr virus has gene with homology to bcl-2 and is one factor in development. • EBV makes B cells proliferate. • EBV genome is found in African Burkitt lymphomas • In other areas, EBV causes infectious mononucleosis.

13. Translocation of c-myc to Ig heavy chain region seen in ~75% of Burkitt lymphoma cases KI 21-3b

14. Tumor antigens • TSTAs -tumor specific transplantation antigens • Expressed exclusively by tumor cells • TATAs - tumor associated transplantation antigens • Variant forms of normal genes • Antigens usually only expressed at certain times or by certain lineages • Antigens overexpressed

15. TSTA and TATAs KI 21-6 CEA, AFP

16. Chemical induction: Different TSTAs for each tumor. No cross protection. Virus induction: Cross protection against tumor cells induced by same virus. No protection if tumor cells induced by a different virus.

17. Immunization against viral induced tumors KI 21-9 a,b

18. CTLs from immunized mouse protects against polyoma-induced tumor cells. KI 21-9 c, d

19. Identification of TSTAs is difficult.The cells with the TSTA do not grow in the mouse but can be detected by CTLs from the mouse. KI 21-7

20. Newer methods to identify TSTAs KI 21-8

21. Immune system selects for tumor cells with low TASA/TSTA KI 21-10

23. Increase costimulation by adding B7 KI 21-11a

24. Increase costimulation by transfection with GM-CSF KI 21-11b

25. Cytokine therapy for cancer • Recombinant cytokines tested • IFNa, b, g, IL-1, IL-2, IL-4, IL-5, IL-12, GM-CSF, and TNF • Problems: complexity of cytokine network, local administration, serious side effects

26. LAK and TIL cells • LAK = lymphokine-activated killer cells • In vitro, culture lymphocytes with tumor antigens and IL-2, reinject the lymphocytes, must infuse IL-2 with LAKs. • TIL = tumor infiltrating lymphocytes • Biopsy tumor, isolate lymphocytes, expand in vitro with IL-2, reinject. • Partial regression

27. Monoclonal antibodies for cancer treatment • Some antibodies may block TSTAs or TATAs- negative effect. • Antiidiotype antibodies to B cell lymphoma were effective but expensive. (fig.22-14) • Anti-HER2 is used to treat breast cancer. • “Magic bullet” idea - use antibody to deliver toxic agent directly to tumor cell.