Interaction between the immune system and tumor

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1 Tumor immunology

2 Interaction between the immune system and tumor elimination (immune system attempts to kill cancer cells and inhibits tumor growth) balance (between elimination and growth of tumor cells) escape (tumor cells sneak out the immunological surveillance)

3 Tumor immunology tumors are immunogenic human body responds immunologically to tumors in a manner similar to the response to transplanted foreign tissues. Facts: The presence of a mononuclear cell infiltrate in situ in inflammatory carcinomas correlates with improved survival rates.

4 Tumor immunology Metastatic cells commonly are present in patients with cancer, but the frequency of their implantation and growth is low After cancer surgery, it is common to detect malignant cells in the blood; however, metastatic implantation is signifocantly less frequent. Cancer patients readily demonstrate immediate and delayed hypersensitivity to autologous tumor-cell extracts in skin reaction tests.

5 Tumor immunology The incidence of malignancy is highest in the neonatal period and in old age, when the immune system functions less effectively. Patients with depressed cell-mediated immunity have an increased incidence of certain malignancies.

6 Tumor immunology The patient with AIDS is particularly likely to have Kaposi's sarcoma Children with certain congenital immunodeficiencies are at increased risk for cancer. In general, there is a three-fold increase in the incidence of cancer in allograft recipients when compared to age-matched controls.

7 Tumor-associated antigens (TAAs) A distinct feature of tumor immunology is that the tumorbearing host is interacting with a source of antigen that is constantly changing. The antigenic profile of the cells is altered such that normally occurring antigens may be lost, whereas new epitopes (neoantigens) emerge. Some human malignancies secrete large amounts of hormones. testicular cancer - human chorionic gonadotropin (hcg).

8 Tumor-associated antigens (TAAs) TAAs may be completely unique to a particular tumor in a specific person. The emergence of these completely unique TAAs often accompanies carcinogeninduced cancers. The carcinogen acts as a mutagen. The tumors induced in different people by a single carcinogen do not have similar antigens, as do malignancies of viral etiology, because of the random occurrence of the mutation.

9 Tumor- specific antigens (TSAs) TAAs are similar in all people carrying a particular tumor; such antigens are commonly termed tumor-specific antigens (TSAs), although in fact they may be found in more than one type of tumor or even in nonmalignant diseases. prostate-specific antigen is found in elevated amounts in the blood of individuals with prostate cancer and in patients with prostatitis.

10 Tumor-associated antigens (TAAs) Some tumors express normal antigens in excessive amounts. myeloma proteins are the immunoglobulin product of the particular B cell that went "out of control" and became malignant - Bence Jones proteins in urine

11 Tumor-associated antigens (TAAs) Similarly, the common acute Iymphoblastic leukemia antigen (CALLA) is abundant in the blood of patients with this most common form of childhood leukemia. Normally, CALLA is expressed only on B-cell progenitors.

12 Tumor-associated antigens (TAAs) Oncofetal antigens are present during normal fetai development but are lost during differentiation of fetal tissue, and they apparently are not synthesized by adults. Oncofetal antigens, however, may reappear during regeneration of the appropriate tissue (e.g., liver) or they may appear as TAAs with the development of malignancy. Two of the most widely studied oncofetal antigens are the α-fetoprotein (AFP) and carcinoembryonic antigen (CEA).

13 Tumor-associated antigens (TAAs) AFP is an alpha globulin that is synthesized and secreted by fetal liver cells. It has 40% homology with serum albumin It reaches fetal concentrations of 3 mg/ml and can be detected in umbilical cord blood.

14 Tumor-associated antigens (TAAs) AFP has been reported to be immunosuppressive, which may be important in the induction of neonatal tolerance to autoantigens. In cell culture, AFP has several effects on T cells: it decreases Th-cell activity and enhances Ts-cell activity.

15 Tumor-associated antigens (TAAs) Most hepatomas secrete large amounts of AFP. AFP also has been detected in the serum of patients with prostatic and gastric carcinomas, teratomas, and embryonal carcinoma of the testes. AFP also may be found in certain nonmalignant conditions, such as cirrhosis of the liver and hepatitis.

16 Tumor-associated antigens (TAAs) Monitoring the changes in the AFP content of a cancer patient's serum provides a prognostic index (or marker) after surgery or chemotherapy. For example, a dramatic increase in the serum concentration of AFP after surgery or chemotherapy signals recurrence of the malignancy.

17 Tumor-associated antigens (TAAs) CEA is detected in the gut, liver, and pancreas of the fetus during the second trimester of pregnancy. low levels in the serum of healthy adults. CEA is associated with several types of cancer: carcinoma of the colon pancreatic carcinoma lung, breast, and prostate gland.

18 Tumor-associated antigens (TAAs) CEA also occurs in several nonmalignant states. 15% of heavy smokers have elevated serum CEA levels. may be elevated in patients with cirrhosis of the liver or chronic lung disease. As in the case of AFP, the utility of CEA lies in its prognostic potential.

19 Tumor-associated antigens (TAAs) Virus-induced TAAs are either component proteins or new enzymes that are induced in the cell to aid in the replication of the virus. Epstein-Barr virus (EBV) antigens have been found in the cells of patients with Burkitt's Iymphoma and nasopharyngeal carcinoma. These patients have high levels of specific antibodies to EBV antigens, which further indicates that Burkitt's Iymphoma and nasopharyngeal carcinoma are induced by this viral agent.

20 Antigens associated with human malignancy Antigen Tumor Viral Hepatitis B Human papilloma viruses 16 nad 18 Ebstein-Barr Human T cell leukemia virus I (HTLV1) Primary liver cancer Cervical carcinoma Burkit s lymphoma, Nasopharyngeal cancer Adult T-cell leukemia Oncofetal Carcinoebryonic Α-fetoprotein Colorectal ca Pancreatic ca Primary liver cancer Tsticular and ovarian ca Gastric and pancreatic ca Other Myeloma proteins Prostate-specific antigen Prostatic acid phosphatase CA-125 glycoprotein Ca19-9 glycoprotein Ca 15-3 glycoprotein Multiple myeloma Prostatic ca Prostatic ca Ovarian ca Pancreatic ca Brest and lung ca

21 Tumor-specific transplantation antigens (TSTAs) TSTAs are a subpopulation of TAAs that can induce a protective immune response in the host if they occur in the membrane of the malignant celi. An appropriate immune response against these immunogens favors the control of a malignancy and elimination of the cancer cells from the body. the cell-mediated immune response is the most efficient tumoricidal mechanism.

22 Immune response to tumor antigens Because the tumor cells have acquired new antigens, they are recognized by the host as foreign. The immune response attempts to rid the body of the tumor cells. the tumor produces soluble antigens, which tend to neutralize these protective responses.

23 Immune response to tumor antigens Immune surveillance. By this mechanism, the body is continuously purging itself of potentially cancerous cells, which are thought to arise frequently during a person's life span.

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25 Immune response to tumor antigens Mechanisms of tumor rejection. Both specific and nonspecific immune responses: humoral and cell-mediated are involved in the rejection of a tumor

26 Immune response to tumor antigens TSTA-specific sensitized T cells constitute the major immunologic barrier against cancer. Tc cells appear in response to antigens such as TSAs or viral antigens. Tc cells can kill tumor cells by direct contact (cytotoxic products).

27 Immune response to tumor antigens Iymphokines macrophages and their tumoricidal activity. Specific antibodies Complement-dependent cytotoxicity can be mediated by antibodies, IgM. When antibody binds to the surface of a tumor cell, the classic complement pathway is triggered, which leads to the eventual destruction of the tumor cell via Iysis, opsonization and intracellular destruction, or release of toxic metabolites and Iysosomal contents with resultant tumor cell destruction.

28 Immune response to tumor antigens The antibodies also may function by "arming" macrophages and neutrophils so that these cells can then react with and destroy the tumor cells. This is exemplified in antibody-dependent cellular cytotoxicity (ADCC), in which the effector NK cells have enhanced affinity for the tumor "target" due to the adhesive action of the antibody molecule.

29 Immune response to tumor antigens NK cells have Fc receptor on the cell surface (FcγRIII, or CD16); the antibody involved is IgG1 or IgG3. When NK cells encounter a tumor cell that has IgG molecules on its surface, the NK cells interact with the "sensitized" tumor cell and destroy it through release of cytotoxic molecules

30 Immune response to tumor antigens NK cells can also kiii tumors by direct contact. Activity non-mhc restricted the cells do not require prior experience with the tumor (antigen) presentation. Once target cell contact has been made, the NK cell releases soluble cytotoxic factors such as perforin, proteases, nucleases, and TNF-α by a process very much like that of the Tc celi. NK cells can be activated by IFN- γ.

31 Immune response to tumor antigens In their normal state, macrophages are not very cytotoxic. However, they can kiii tumor cells when activated. Antibodies to TSAs may bind simultaneously to tumor cells and macrophages through the antigen-binding site on the former and the Fc-γRI and Fc-γRII receptors on the latter. This forms a bridge that activates macrophagemediated cytotoxicity, which leads to death of the tumor celi.

32 Immune response to tumor antigens In vivo, sensitized T cells are triggered to release macrophage-activating factors, which interact with macrophages, changing their metabolism and making them potent killers of tumor cells. The two major activators are IFN-γ and TNF-α.

33 Immune response to tumor antigens macrofages Activated macrophages do not rely on interacting with any specific tumor antigen; however, like NK cells, they do seem to distinguish malignant from normal cells. Macrophages produce many antitumor products: Hydrolytic enzymes

34 Immune response to tumor antigens macrofages IFN-α, which acts indirectly by activating NK cells TNF- α (cachectin), a protein that induces other cells to release IL-l, IL-6, IL-8, and IFN. Locally, TNF-α increases T-cell adhesion to the vascular endothelium and activates these cells to heightened cytotoxicity. Systemically, TNF- α causes fever and synthesis of acute-phase proteins

35 Immune response to tumor antigens macrofages Hydrogen peroxide, and other oxidative products of the glycolysis, can be directly toxic to tumor cells by disturbing the cell membrane. Nitric oxide (NO) toxic to tumor cells bacteria importance in controlling parasitic infections(toxoplasmosis). For optimal expression of this pathway, macrophages need to be stimulated by both IFN-γ and TNF.

36 Immune response to tumor antigens Innate Immune Processes Macrophages Natural killer cells Acquired Immunities Humoral - Opsonic antibodies, Complementactivating antibodies, Antibody-dependent cellular cytotoxicity Cell mediated Cytotoxic T cells DTH T cells Soluble mediators Interferon-γ Tumor necrosis factors α and β

37 Immunologic factors favoring tumor growth Tumor cell attributes often allow a tumor to escape immune destruction Tumor antigenic heterogenecity faciiitates tumor survival. Modulation of tumor antigenicity occurs when antibody to the tumor cell reacts with the appropriate antigens on the tumor cell surface. If the antibody is cytotoxic, tumor cells expressing the homologous antigen are destroyed. This favors the emergence of tumor cells whose membranes have a different antigenic mosaic. Tumors release immunosuppressive factors such as AFP and prostaglandin E2.

38 Immunologic factors favoring tumor growth Blocking factors also may enhance tumor growth. The serum of cancer patients often contains soluble TSTA or TSTA-antibody complexes, which react with (i.e., "block") the tumor-specific receptors on sensitized T cells, thereby preventing their cytotoxic interaction with tumor cells. Ordinarily, TSTA in the groove of a class I MHC molecule interacts with the tumor antigen recognition site on the T- cell surface. This triggers the cytotoxic activity of the T celi.

39 Immunologic factors favoring tumor growth Free tumor antigen could interact with the T-cell receptor and actually not trigger the T cell but prevent it from recognizing and attacking the tumor celi. Soluble TSTA also can react with cytotoxic antibody before the cytotoxic antibody can attach to the tumor cell and sensitize it to ADCC killing.

40 Immunologic factors favoring tumor growth tumor-specific immune complexes The most potent blocking factors in serum are the tumor-specific immune complexes. (act like free tumor antigen, mask the tumor recognition sites of T cells) paralyze the T cells and keep them in a state of nonreactivity

41 Mechanisms by which Tumors Escape the Immune Response of the Host Tumor is nonimmunogenic Tumor modulates its surface antigens Loss of class I MHC molecules Loss of adhesion molecules Tumor secretes imunosuppressive molecules Tumor induces an immune response that protects the tumor cell from destruction No immune response occurs Tumor changes antigens to avoid immune destruction Tumor cannot be destroyed by MHC-restricted cytotoxic T cells Cytotoxic T cells cannot attach effectively to tumor cell membrane Immune response is downregulated Tumor-growth-enhancing antibodies react with tumor TST As and prevent the interaction of these TST As with protective immune factors; suppressor cells interfere with the induction of a protective immune response

42 Immunologic factors favoring tumor growth Other factors favoring tumor growth: Ontogenic status. The immune response is poorly developed or very weak in people at certain times of life. Neonates and the elderly have the highest incidence of maiignancy. Immunological deficiency may be hereditary or may be induced by such factors as irradiation, infection (e.g., with HIV) or immunosuppressive drugs. The incidence of malignancy is greatly increased in immunodeficient people.

43 Immunotherapy Immunotherapy has been used as adjunct to traditional treatments. Both active and passive means of stimulating the non-specific and specific immune systems have been employed, in some cases with significant success.

44 Immunotherapy of tumors active non-specific specific BCG, Propionibacterium acnes, cytokine genes killed tumor cells or their extract, recombinant antigens, idiotype, co-stimulatory molecule genes, etc. passive nonspecific specific LAK cells, cytokines antibodies alone or coupled to drugs, pro-drug toxins or radioisotope; bispecific antibodies; T-cells combined LAK cells and bispecific antibody

45 Immunotherapy Principles of treating humans with tumors include: Reduction of the tumor "Ioad" by surgery, chemotherapy, or both Modification of tumor cells to enhance their antigenicity and eliminate their viability Activation of the immune response through the use of adjuvants

46 Immunotherapy Immunotherapeutic modalities Immunotoxins Tumor-specific monoclonal antibodies conjugated to tumoricidal substances, such as radionuclides or toxins (e.g., diphtheria toxin, ricin), administered by injection. The monoclonal antibodies carry the therapeutic agent directly to the tumor, which lowers toxicity to normal tissues.

47 Immunotherapy Macrophage-activating compounds 1. BaciIle Calmette-Guerin (BCG), the mycobacterial vaccine used to immunize people against tuberculosis 2. Muramyl dipeptide, a synthetic peptide that mimics the action of mycobacteria

48 Cytokine therapy of tumors Cytokine Tumor type and results Anti- tumor mechanism/s IFN-α and β remission of hairy cell leukemia, weak effect on some carcinomas increased expression of class I MHC,, possible cytostatic anti-tumor effect, IFN-γ IL2 TNF-α remission of peritoneal carcinoma of ovary: ineffective systemically remission in renal carcinoma and melanoma can reduce malignant ascites increased MHC antigens; macrophage, Tc and NK cell activation T-cell proliferation and activation, NK cells activation macrophage and lymphocyte activation

49 Immunotherapy Cytokine genes, increase the immunogenicity of cancer cell vaccines in experimental animals The gene encoding granulocyte-macrophage colony stimulating factor promotes the development of dendritic cells at the site of vaccine deposition. The dendritic cells initiate the most potent T-cell response. The genes cause production of large amounts of the protein locally. Introduction of the Il-12 gene into cancer cell vaccines also enhances the development of cell-mediated immune responses. Heat shock proteins purified from bacterial cells - excellent adjuvants when mixed with TST As.