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part 2. mechanisms of carcinogenesis

chapter 16. Immunosuppression Jerry M. Rice PART 2 CHAPTER 16

Introduction from exposure to non-viral antigens, pharmaceutical drugs or by ionizing such as after or ultraviolet radiation is dose-de- Immunosuppression is a reduction (Ponce et al., 2014). pendent – the intensity and duration in the capacity of the immune sys- Potentially neoplastic cells that of the effect increases with increasing tem to respond effectively to foreign arise naturally, or that have been dose or continuing exposure – and is antigens, including surface antigens transformed by carcinogens acting usually transient: immune function on tumour cells. Immunosuppression by a mechanism such as genotox- generally recovers after cessation can result from killing of immune ef- icity or by the various mechanisms of exposure. In contrast, fector cells or from blockage of intra- of action associated with oncogenic with certain , such as hu- cellular pathways essential for anti- viruses, may escape immune sur- man virus type 1 gen recognition or of other elements veillance in immunosuppressed indi- (HIV-1) or malaria parasites, is per- of the immune response. viduals. As a result, survival of these sistent, and the immune deficiency Persistent immunosuppression cells and their replication to form that results is progressive unless the presents a risk of . Individuals tumours is greatly facilitated. infection is effectively treated. who are latently infected with an on- Certain pharmaceutical drugs, Immunosuppression as a medi- cogenic virus are at greatly increased ionizing and ultraviolet radiation, cal is used to treat autoim- risk for developing virus-related or infection with certain viruses mune diseases such as ery- when they become immu- and parasites can cause immu- thematosus or . nosuppressed (Grulich et al., 2007; nosuppression. After exposure to Immunosuppressive drugs, usually Schulz, 2009; Wieland et al., 2014), X-rays or other types of ionizing in much higher dosage, are used to and there is excess risk of B-cell radiation, immunosuppression is maintain the functional and anatom- non-Hodgkin lymphoma (NHL) when most pronounced if the entire body, ical integrity of foreign tissues graft- immunosuppression is accompanied rather than a limited area, is irra- ed onto another individual, such as by continuing immune stimulation diated. Immunosuppression by a kidney or heart transplant. A graft

Part 2 • Chapter 16. Immunosuppression 159 from any individual except oneself and solar radiation, and most of the leukaemia by a genotoxic mech- or an identical twin will provoke an chemical alkylating agents used in anism after its use in anticancer immune reaction against the graft- anticancer . Radiation chemotherapy (IARC, 2012b). ed tissues, the intensity of which and chemical alkylating agents are varies with the degree of antigenic considered to cause cancer primar- Immunosuppressive difference between graft and host. ily by inducing DNA damage, rather carcinogens In the absence of adequate immu- than by immunosuppression. Several Group 1 agents reviewed in nosuppression, the host will destroy is an anti- Volume 100 of the IARC Monographs the graft. Whole organs (e.g. kidney, neoplastic drug and is classified as act entirely or largely by immuno- heart, liver, or lung) can be trans- carcinogenic to humans (Group 1). suppression, often in concert with planted with maintenance of func- This drug has very marked immuno- other Group 1 agents, especially tion that may continue for a normal suppressive properties. In addition to oncogenic infectious agents. The lifetime when appropriate levels of its application in anticancer chemo- Group 1 agents that act by immuno- immunosuppression are maintained. therapy, cyclophosphamide is used suppression are HIV-1 and the phar- However, the risk of primary cancer clinically as an immunosuppressant maceutical drugs and in the transplant recipient increases to treat certain autoimmune diseas- . with increasing intensity and dura- es, such as severe systemic lupus tion of immunosuppression (Kinlen, erythematosus (Valeri et al., 1994). HIV-1 infection 1996; Yu et al., 2014). The drug, which must be metabo- An uncommon but potentially lized to act as an alkylating agent, Infection with HIV-1 is the cause of dangerous side effect of immuno- causes acute myeloid leukaemia and the acquired immune deficiency syn- suppression to support organ trans- carcinoma of the urinary bladder in drome (AIDS). The severe immune plants is that suppression of the patients in whom it has been used deficiency that is characteristic of immune response can allow occult as an antineoplastic agent (IARC, AIDS results from a deficiency in tumours or metastatic tumour cells 2012b). All available evidence, in- CD4-positive T lymphocytes and within the transplanted tissues or cluding the organ sites of tumour a severe loss of memory B cells (IARC, 2012a). In addition to severe organs to survive, grow, and me- development and the specific kinds , several cancers occur at tastasize in the transplant recipient. of neoplasms induced, indicates high frequency in patients with AIDS. Occult metastatic in the that cyclophosphamide exerts its NHL, especially primary brain NHL, donated organ is especially dan- carcinogenic activity via a genotoxic as well as Kaposi sarcoma and cer- gerous for the transplant recipient mechanism (McCarroll et al., 2008), vical carcinoma are AIDS-defining (Penn, 1996; Loren et al., 2003). rather than via immunosuppression. conditions in severely immunosup- Such transplanted cancers regress Chlorambucil, like cyclophos- pressed patients. when immunosuppressive therapy is phamide, is a bifunctional alkylating There is no evidence that HIV- withdrawn (Wilson et al., 1968; Loren agent that also is an antineoplastic 1 causes NHL or other cancers et al., 2003). drug and is classified as carcinogen- ic to humans (Group 1). It is used clin- through a direct effect. Unlike what is Immunosuppression and ically as an immunosuppressant to known about other cancer-associat- genotoxicity treat childhood nephrotic syndrome ed viruses, there is no evidence that (Neuhaus et al., 1994), rheumatoid HIV-1 infection by itself leads to cell The fact that a carcinogen has im- arthritis, and other autoimmune dis- transformation or immortalization. munosuppressive properties does eases. It has been used to treat poly- The HIV-1 genome is not present not necessarily mean that this is the cythaemia vera (a ) and in cancer cells, in contrast to what mechanism by which it causes human is used, often alone, as initial therapy is observed with infectious agents cancer. DNA-damaging agents are for chronic lymphocytic leukaemia that are directly oncogenic (IARC, generally also immunosuppressants, and in combination with other drugs 2012a). especially at high levels of exposure; to treat other cancers. Chlorambucil, Kaposi sarcoma, which is caused these include external ionizing radi- like other antineoplastic alkylating by Kaposi sarcoma herpesvirus ation (X-rays and γ-rays), ultraviolet agents, can cause acute myeloid (KSHV), is the most common cancer

160 in patients with HIV-1 infection. Its virus and hepatitis C virus, and are al population (Kasiske et al., 2004). occurrence is highly correlated with therefore at elevated risk for hepa- Non-melanoma skin cancers other the severity of suppression of CD4- tocellular carcinoma (Grulich et al., than Kaposi sarcoma also occur at positive T lymphocytes. The stan- 2007). high frequency in organ transplant dardized incidence ratio for Kaposi recipients (Forchetti et al., 2014). Therapeutic sarcoma in a Swiss cohort was more There is a 65-fold increase in the immunosuppression than 500 in patients with a CD4- incidence of squamous cell carci- positive lymphocyte count of less Therapeutic immunosuppression, noma and a 10-fold increase in the than 100 cells/mm3 but approximate- generally by various combinations incidence of basal cell carcinoma in ly 76 in patients with a CD4-positive of drugs such as ciclosporin and organ transplant recipients relative lymphocyte count of greater than azathioprine, is administered to or- to the general population (Yu et al., 500 cells/mm3 (Clifford et al., 2005; gan transplant recipients to maintain 2014). IARC, 2012a). their transplanted organ or organs. Ciclosporin NHL, chiefly of the B-cell type, Recipients are at high risk for some is the second most common ma- of the same cancers that occur in Ciclosporin, a cyclic lipophilic un- lignancy in patients with AIDS. In a patients with AIDS. A comparison decapeptide, is a calcineurin inhibi- meta-analysis of six studies, NHL of AIDS-related and transplanta- tor and a potent immunosuppressant had a standardized incidence ratio tion-associated tumours, from which that is virtually non-myelotoxic but PART 2 of 77 in patients with HIV-1 infection this text is excerpted, is presented in is markedly nephrotoxic. It is used CHAPTER 16 relative to the general population IARC (2012a). in organ and tissue transplanta- (Grulich et al., 2007), and NHL is Although individuals with AIDS tion to prevent graft rejection after frequently associated with Epstein– and those with iatrogenic immuno- marrow, kidney, liver, pan- Barr virus (EBV) co-infection. The suppression after organ transplan- creas, heart, lung, and heart–lung severe depletion of CD4-positive T tation have immunodeficiency in transplantation, and for prophylaxis lymphocytes induced by HIV-1 leads common, the immunological abnor- and treatment of graft-versus-host to dysregulated control of B lympho- malities appear to differ consider- disease (IARC, 2012b). cytes and to the expression of co-in- ably between these two conditions. The immunosuppressive activity fecting lymphotropic viruses (Engels, However, the spectra of neoplasms of ciclosporin is consistent with an 2007). that occur in patients with AIDS and increased risk of cancer as a result The third most common malig- in organ transplant recipients large- of impaired immune surveillance, nancy in HIV-1-positive individuals, ly overlap. An obvious similarity be- particularly for virus-related can- and also an AIDS-defining condition, tween organ transplant recipients cers such as EBV-related NHL and is cervical carcinoma associated and patients with AIDS is the in- HPV-related cervical cancer (IARC, with human papillomavirus (HPV) creased incidence of B-cell NHL as- 2012b). Patients who receive ciclo- infection. Anogenital intraepitheli- sociated with EBV infection. Specific sporin also are at increased risk for al neoplasms and carcinomas are differences include more frequent squamous cell tumours of the skin, also increased in frequency, and so high-grade lymphomas in patients which may be due in part to effects are skin cancers associated with with AIDS and a more frequent EBV of the drug other than immunosup- HPV infection (IARC, 2012a). In ad- association and polymorphic lesions pression. Ciclosporin has the ability dition to NHL and Kaposi sarcoma, in organ transplant recipients. to generate reactive oxygen species, infection with HIV-1 causes cancer The second important malignan- and this is probably relevant to its of the cervix, anus, and conjunctiva, cy that is greatly increased in inci- carcinogenicity (IARC, 2012b). as well as of the vulva, vagina, and dence in both individuals with HIV-1 Azathioprine penis (IARC, 2012a). The primary infection and transplant recipients is cause of these squamous epithelial Kaposi sarcoma (Zattra et al., 2014). Azathioprine, a substituted 6-mer- neoplasms is co-infection with HPV. A study of renal transplant recipi- captopurine, is used in immunosup- Finally, individuals with HIV-1 infec- ents reported a more than 20-fold pressive treatments to prevent re- tion have a greatly increased inci- increase in the incidence of Kaposi jection of kidney allografts. The drug dence of infection with hepatitis B sarcoma compared with the gener- is usually used in conjunction with

Part 2 • Chapter 16. Immunosuppression 161 other immunosuppressive therapy, disorders that generally have a viral immune protection associated with including local and etiology; and (ii) because it caus- prenatal or chronic exposure to P. fal- treatment with and es 6-thioguanine to accumulate in ciparum is common in children living other cytotoxic agents. patients’ DNA, it also contributes to in malaria-endemic regions (Chelimo One large prospective cohort cancer development by induction of et al., 2005; Scott et al., 2005). study (Kinlen et al., 1979) on renal DNA damage (IARC, 2012b). Children in certain regions of transplant recipients who received Often, milder therapy and less Africa become infected with EBV ear- azathioprine examined the incidence potently immunosuppressive drugs ly in life, and nearly all have serocon- of and mortality from different types (e.g. such as prednisone) verted by age 3 years (Biggar et al., of cancer compared with the num- are used for autoimmune conditions 1978). EBV is activated when the bers expected on the basis of the than for maintenance of organ trans- is compromised (re- incidence and mortality rates for plants. Prednisone and related im- viewed by Hopwood and Crawford, the relevant country (Australia, New munosuppressive drugs have 2000). Endemic Burkitt lymphoma Zealand, and the United Kingdom). not been shown to be carcinogenic. (eBL), the most common paediatric An almost 60-fold increase in the cancer in sub-Saharan Africa, is a Malaria, a probable human risk of NHL was observed for all high-grade B-cell lymphoma char- carcinogen countries combined (34 observed, acterized by the consistent presence of EBV (Epstein et al., 1964, 1965; 0.58 expected), as well as a 30-fold In addition to the IARC Group 1 zur Hausen et al., 1970). eBL occurs increase in the risk of squamous agents that are carcinogenic large- only where malaria transmission cell in patients from the ly or entirely by an immunosup- intensity is high, for example in the United Kingdom (3 observed, 0.13 pressive mechanism, infection with so-called lymphoma belt of sub-Sa- expected) (IARC, 2012b). Plasmodium falciparum malaria in haran Africa and in the high-trans- Azathioprine is used more often holoendemic areas is probably car- mission areas of Papua New Guinea. in individuals with autoimmune con- cinogenic to humans (Group 2A), at Furthermore, within areas and coun- ditions than in transplant recipients. least in part by immunosuppression tries where eBL occurs, it arises only For example, azathioprine is given (Bouvard et al., 2012; IARC, 2014). among those living in regions with for management of the signs and Infection with P. falciparum malar- the highest transmission intensity, symptoms of rheumatoid arthritis in ia has immunosuppressive effects, the so-called holoendemic or hyper- adults (IARC, 2012b). Excesses in as reflected by impairment of mac- endemic areas. P. falciparum can the risk of NHL (relative risk, 10.9) rophage function and antigen pres- disturb the immature immune system and of squamous cell skin cancer entation (dendritic cell inhibition), in young children by expanding the (relative risk, 5.0) were found in reduction in specific T-cell response, B-cell pool in which eBL arises, and non-transplant patients receiving induction of regulatory T cells, and can reactivate latent EBV. Infection azathioprine, although these ex- high plasma levels of pro-inflamma- with both EBV and P. falciparum is cesses are smaller than those in tory cytokines (interleukin 6 [IL-6] required for the development of eBL transplant recipients (Kinlen, 1985). and tumour factor alpha (Bouvard et al., 2012; IARC, 2012a). Azathioprine is carcinogenic via [TNF-α]) and regulatory cytokines two mechanisms: (i) as an immu- (IL-10 and tumour growth factor beta nosuppressant, it is associated with [TGF-β]) (reviewed by Cunnington post-transplant lymphoproliferative and Riley, 2010). Impaired humoral

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Part 2 • Chapter 16. Immunosuppression 163