The immune system, infection, and the prevention of cancer Epidemiological clues from transplant...
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The immune system, infection, and The immune system, infection, and the prevention of cancer the prevention of cancer
Epidemiological clues from transplant Epidemiological clues from transplant recipients and people with AIDSrecipients and people with AIDS
Andrew GrulichAndrew Grulich
UNSW Medical Faculty Dean’s Lecture, September 2007 UNSW Medical Faculty Dean’s Lecture, September 2007
National Centre in HIV Epidemiology and Clinical Research, University of New National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia. South Wales, Sydney, Australia.
OutlineOutline
BackgroundThe known role of infection in the causation of cancer
What can we learn from immune deficient populations? Studies in transplant recipientsStudies in people with HIV/AIDS
Two examples What causes Kaposi’s sarcoma? What causes non-Hodgkin’s lymphoma?
Future directions and interventions
Viral agent IARC: Evidence of causality
Sufficient Limited Inconclusive
Hepatitis B Liver
Hepatitis C Liver
HTLV-1 Adult T-cell lymphoma
HHV8 Kaposi’s sarcoma
Primary effusion lymphoma
Epstein-Barr Nasopharynx Salivary gland
virus (EBV) Hodgkin’s disease Stomach
non-Hodgkin’s lymphomaa Lung
Established virus-cancer relationshipsEstablished virus-cancer relationships
aIn immune suppressed populations
Viral agent Evidence of causality
Sufficient Limited Inconclusive
Human papillomavirus CervixAnusVulva
VaginaPenis
TongueTonsil
Non-melanoma skinPeri-ungal skin
LarynxEye
Nasal cavity
Colon
Lung
Breast
Ovary
Prostate
Bladder
Mouth
Oropharynx
Established virus-cancer relationshipsEstablished virus-cancer relationships
Agent IARC: Evidence of causality
Sufficient Limited Inconclusive
Helicobacter pylori StomachGastric B-cell
MALT
Schistosoma haematobium
Bladder
Opisthorchis viverrini Cholangio-carcinoma
Other infective agents and cancer Other infective agents and cancer
The magnitude of the effectThe magnitude of the effectAgent Cancer No. of
cases% of cancers
at that site% of all cancers
H pylori Stomach Lymphoma
592,000 11,500
63%75%
5.5%
HPV Cervix Anogenital Mouth, pharynx
492,80053,88014,500
100% 5.2%
HBV and HCV Liver 535,000 85% 4.9%
EBV Nasopharynx Hodgkin lymphoma Burkitt lymphoma
78,10028,6006,700
98% 1.0%
HIV/HHV8 KS NHL
66,20036,100
100% 0.9%
Schistosomes Bladder 10,600 3% 0.1%
HTLV-1 ATL 3,300 >90% 0.03%
Liver Flukes Cholangio-carcinoma 2,500 0.02%
Parkin et al, Int J Cancer, 2006
How does infection cause cancer?How does infection cause cancer?
Direct effects of virally-encoded proteinsHPV
E6 inactivates P53 by inducing rapid degradationE7 activates cyclin dependent kinase 2
HTLV1Tax transcriptionally activates a variety of oncogenes
EBVLMP1 up-regulates BCL2 and a range of cellular oncogenes
Indirect effects HBV/HCV
Not directly oncogenicCarcinogenicity may depend on the immune response
H pylori and flukesNot directly oncogenic?chronic inflammation
Summary: the role of infection Summary: the role of infection
Infection is acknowledged as having an important role in the causation of cancer
Over the past 25 years, the proportion of all cancers thought to be infection-related has increased from around 5% to close to 20%
Discoveries have arisen mainly from the study of single agent-single cancer associations
What can the study of immune deficient populations add?
Immune deficient populations Immune deficient populations
Impaired immunity can unmask the carcinogenic effects of infection
The interlinked effects of infection and immunityThe interlinked effects of infection and immunity
The effects of infection and of impaired immunity are linked
Impaired immunity leads to increased clinical expression of infectious diseases
Increased replication of infective agents and an increased risk of those cancers related to infection
The relationship may be more complex when carcinogenesis depends on a robust immune response
eg liver cancer, stomach cancerWhen the cancer arises from cells of the immune system
B lymphocytes (90% of lymphoma)T lymphocytes Others (rare)
Sir Frank Macfarlane Burnet
Nobel Prize, 1960
Immunological surveillance:
“small accumulations of tumour cells may develop, and because of their possession of new antigenic potentialities, provoke an effective immunological reaction with regression of the tumour, and no clinical hint of its existence”
Cancer - a biological approach, 1957.
1950’s: immune surveillance theoryImmunity essential for the recognition and elimination of emerging cancer clonesImpaired immunity should result in increased risk of all cancer types
1970: the advent of post-transplantation immune suppressionIncreased rates of Kaposi’s sarcoma and NHL noted immediatelyLittle evidence of other increases
1980: the advent of AIDSIncreased rates of Kaposi’s sarcoma and NHL noted immediatelyInconsistent evidence of other increases
2000+: larger populations of people with HIV and transplant recipientsAre other cancers associated with immune deficiency?Might these populations provide a way to allow new discoveries of infectious causes of cancer?
Immune deficiency and cancer: historyImmune deficiency and cancer: history
How do we study whether cancer occurs at increased rates in people with immune deficiency?
Clinical cohort studies Relatively expensive, of limited power thus far
“Linkage” studiesLink identifiers of people with HIV/AIDS, or transplant recipients, with cancer registersCompare rates of cancer to those in the general population using the SIRWhere such databases exist, these effectively create a population-wide cohort study
Australia’s advantagelongstanding and nationwide HIV and transplant registration and cancer registration
A comparison of the pattern of cancer in transplant recipients with cancer in people with HIV/AIDS has the potential to help guide our thinking about which cancers we might expect to occur at increased risks in people with impaired immunity
Study design: immune suppression and cancerStudy design: immune suppression and cancer
Cancer in transplant recipients Cancer in transplant recipients
By the year 2000, there was General agreement that there are markedly increased rates of Kaposi’s sarcoma and non-Hodgkin lymphoma
A study from Sweden in the late 1990’s suggested a wider range of cancers occur at increased rates
There was a lack of agreement on which cancers occur at increased rates, and whether or not these might be related to factors which also caused end stage renal disease
New, potentially less carcinogenic compounds being trialled for use in immune suppression (m-TOR inhibitors)
Methods Data linkage
Name-based, probabilistic
Retrospective population-wide cohort study, 1982-2002Data linkage between:
Australia and New Zealand Dialysis and Transplant Registry (ANZDATA)
Population-based register of renal transplantation, since 1960’sEnter register at dialysis for end stage renal disease
National Death Index (NDI)Population-based register of all deaths in Australia
National Cancer Statistics Clearing House (NCSCH)Population-based register of cancers occurring nationally, since 1982
Cancer in Australian kidney transplant recipientsCancer in Australian kidney transplant recipients
MethodologyMethodologyStudy populationStudy population
ANZDATA extract n=31,446
Australian residents
Remove if no/partial follow-up in Australia (n=378)
Registered/alive during study period
Remove if registered/died prior to01/01/1982 (n=2,208)
Remove if registered after enddate (n=5)
n=31,068
n=28,855
ResultsResultsCohortCohort characteristics characteristics
Characteristics No. of registrants (%)
Person-years
Mean person-years
Mean age
Total 28,855 (100)
273,407
9.5 49.2
Time periods
Prior to treatment 25,685 (89) 119,279
4.6 49.5
Dialysis 24,926 (86) 67,231 2.7 54.2
After transplantation
10,180 (35) 86,898 8.5 41.0
Results: virusesResults: viruses
All cancersUnspecified
LeukemiaNon-Hodgkin lymphoma
Hodgkin diseaseThyroid
BrainEye
TestisProstate
PenisOvary
Corpus uteriCervix uteri
VulvaBreast
Connective tissueKaposi sarcoma
MesotheliomaMelanoma
LungLarynx
PancreasGallbladder
LiverAnus
RectumColon
Small intestineStomach
EsophagusSalivary gland
MouthTongue
Lip
.01 .1 1 10 100 1000 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000
Prior to RRT During dialysis After transplantationS
ite
SIR
Sufficient evidence Limited evidence Inconclusive evidenceVajdic et al, JAMA, 2006
Kidney transplantation is associated with increased cancer risk across a number of sites
For most of these, cancer risk was not increased prior to transplantation
Most, but not all, were cancers with a known or suspected viral cause
These data suggest an important role of the interaction between common viral infections and the immune system in the aetiology of a large variety of types of cancer
Summary
How does this compare to HIV?
NHL, KS and cervical cancer are recognised as part of the definition of AIDS
A variety of other cancers occur at increased rates in people with HIVAnal Cancer (RR 40, only in gay men)Leiomyosarcoma in children (RR > 50)SCC of the conjunctiva (RR 10-20)Hodgkin disease (RR about 10) Lip cancer (RR at least 5)
Grulich et al, AIDS, 1999; Engels et al, AIDS, 2006.
Based on the largest single study, the US AIDS-cancer match, these were not associated with immune deficiency
The authors concluded that lifestyle factors , and not immune deficiency, likely explain these increased risks
Frisch et al, JAMA, 2001.
Are these cancers associated with i-deficiency?
US AIDS-cancer matchA cancer is judged as AIDS-related if
SIR increased for the entire period from 5 years before until 2 years after AIDSIncreasing trend of SIRS pre to post AIDS
Many cancers increased overallfew had an increasing trend from early to late stagesproblem: in the era of effective HIV therapy a pre-post AIDS comparison may not represent increasing immune deficiency
A new approach Which cancers occur at increased rates in people with HIV? How does this compare to transplant recipients?If the pattern is similar, then it is likely to be immune deficiency, and not shared lifestyle factors, which increase cancer risk
HIV-cancer studiesHIV-cancer studies
Grulich et al, Lancet, 2007
Transplant studiesTransplant studies
Grulich et al, Lancet, 2007
Infection-related cancersInfection-related cancers
Grulich et al, Lancet, 2007
Infection-related cancers 2: HPVInfection-related cancers 2: HPV
Common epithelial cancersCommon epithelial cancers
Grulich et al, Lancet, 2007
Other cancers increased in one or bothOther cancers increased in one or both
Grulich et al, Lancet, 2007
ConclusionConclusionA new approach to determine the range of immune deficiency-related cancer
A much larger range of cancers than previously appreciated is associated with transplant and HIV-associated immune deficiency
Most, but not of all of these, are infection-related, and HPV plays a prominent role
The lack of association with immune deficiency in the US AIDS-cancer match may mean that these cancers occur at relatively preserved CD4 counts
The association with degree of immune deficiency may well not be linear, and appears to be different for different cancers
Considerations of increased cancer risk in mild immune deficiency may influence the question of “when to start” HIV therapy.
What causes Kaposi’s sarcoma?
Kaposi’s sarcomaKaposi’s sarcoma
A malignancy arising from lymphatic endothelial cells
Gives rise to darkly pigmented lesions of the skin and mucous membranes
Lesions can occur anywhere on skin, and are frequently disfiguring
Involvement of internal organs (respiratory and GI tract) can lead to bleeding and death
KS in AIDS KS in AIDS
KS was the harbinger of the AIDS epidemic
Relative risk of 50,000 or more
Percent of AIDS defining illnesses Developed countries
male homosexuals 30-40% all others < 5%
African heterosexuals 20% +
Risk of KS is raised in homosexual men who report More sexual activityA history of sexually transmissible infections
Consistent with a sexually transmissible agent
The cause of KS: human herpesvirus 8The cause of KS: human herpesvirus 8
Discovered in KS tissue in 1994
Discovered by a molecular biologist-epidemiologist team
A gamma herpesvirus, found in close to 100% of KS tissue, rarely described in control tissueinfection precedes development of KS
HHV-8/KSHV is now recognised as the cause of KS Close relatives found in African green monkeys, other primates Closest human relative is Epstein Barr Virus Probably an ancient cross species transmission
Chang et al, Science, 1994
Risk factors for HHV8 in people with HIV
Homosexual men with serological evidence of HHV-8 infection:Report more STDs
Report twice as many casual partners
Significantly more likely to report sexual risk behaviours with casual partners
More likely to be HSV2 IgG positive
ie a sexually transmissible infection
HHV-8 serology predicts future development of KSGrulich et al, J AIDS & HR, 1999
PathogenesisPathogenesis
HHV-8 is the necessary cause of KS.
It contains a several recognisable host genes (“molecular piracy”).
The proteins encoded by these genes include some that are homologous to human oncoproteins.
a cyclin that inhibits retinoblastoma proteinbcl 2 like protein that prevents apoptosis.G protein coupled receptoran inhibitor of apoptosis mediated by the FLICE pathway an inhibitor of the interferon signalling pathwayIL-6 (induces B cell proliferation)three functional chemokines (?Angiogenic)
Products encoded by viral genes directly de-rail cell cycle control
Stopping HHV8 replication should stop carcinogenesis
KS: a story (almost) solved KS: a story (almost) solved The extra-ordinarily distinctive epidemiology of immune deficiency and of infection with HHV-8 among people with KS led us to the cause
Incidence has plummeted in developed countriesKS is essentially an opportunistic infection associated with loss of cell-mediated immunity against HHV-8HHV-8 is under very close control by the immune system: maintenance of immunity prevents KS development
When KS presents clinically in a person with HIV, first line therapy is usually anti-retroviral therapy (ARV)
Restoration of anti-HHV-8 immunity mostly results in tumour regressionThis challenges our concept of what is a malignancy
KS remains an enormous issue in those sub-Saharan African countries where ARV therapy access is poor and HHV-8 seroprevalence is high
Now the most common cancer in sub-Saharan Africa
KS in SE Sydney, 1972-99KS in SE Sydney, 1972-99
0
5
10
15
20
72 74 76 78 80 82 84 86 88 90 92 94 96 98
Rat
e p
er 1
00,0
00
KS incidence
1. Age standardised to Australian population 1991
Source: NSW Cancer Council
Sexually a51.951.453.757.648.556.556.9
HIV epidemic
KS mainly in homosexual men
KS and sexual transmission
Discovery of HHV-8
Combination therapy
What causes non-Hodgkin lymphoma?
Non Hodgkin LymphomaNon Hodgkin Lymphoma
A cancer arising from lymphocytes and presenting as a mass
If presenting in the blood = leukaemia
Common cause of cancer death with incidence rapidly increasing (?recent plateau)
6th most common cause of cancer death in Western countries
It mainly involves B, not T, lymphocytes (also in HIV)ie not the target cells for HIV infection
Risk factors largely unknown; immune deficiency important
Rate increased 10 fold in immune suppressed transplant recipients
3-5% of AIDS-defining illnessesprobably more than 10% of AIDS deaths in Western settings
50-100x more common than general population
Unusual subtypes, aggressive (“high grade”) and often rapidly fatal
Burkitt’s: mild immune deficiency (median CD4 300+)Large cell-immunoblastic: severe i-deficiency (CD4 50)Primary CNS: profound immune deficiency (CD4 10)
EBV present in 20% of Burkitt’s lymphoma, 50%+ of LCI NHL and 100% of CNS NHL
Little variation in risk with route of HIV infection Therefore unlikely to be due to a STI or a BBV
NHL in AIDSNHL in AIDS
Risk factors: NSW case-control studyRisk factors: NSW case-control study
Design
Cases: 219 people with AIDS NHL in Sydney, 1984-94
Controls: 219 people with HIV infection without NHL
Matched: degree of immune deficiency (CD4 count)
Data: medical record reviewSerial CD4 countsLong term markers of B cell stimulation (serum Ig, globulin)Therapies active against EBV
Grulich et al, AIDS, 2000
CD 4 count one year prior to match date
CD4 count Odds Ratio 95 %CI<20 1.020-99 1.04 0.51-2.12100-199 0.51 0.24-1.05200-499 0.50 0.25-0.99500 0.48 0.19-1.16
p trend 0.003
Duration of immune deficiency Duration of immune deficiency
Grulich et al, AIDS, 2000
Long term B cell stimulationLong term B cell stimulation
30
32
34
36
38
40
0 1 2 3 4 5
Years prior to match date
Mea
n se
rum
glo
bulin
Cases Controls
n cases 216 108 67 47 28 20
n controls 201 110 63 42 23 16
Grulich et al, AIDS, 2000-
Indices of the role of EBVIndices of the role of EBV
Anti-herpes drugs in the previous year Acyclovir OR 1.06 (95% CI 0.65-1.71)
no dose effectno subtype effect
Ganciclovir OR 0.51 (95 % CI 0.20-1.25)
Effective anti-EBV therapy does not prevent AIDS-NHL
Grulich & Law, Clin Inf Dis, 2001
AIDS-NHL in the era of effective ARV therapyAIDS-NHL in the era of effective ARV therapy
Incidence decliningCNS NHL is disappearing in areas where HAART access is universal
an opportunistic infection due to lack of cell mediated immunity against EBV. restoration of CMI against EBV prevents, and in some cases cures, CNS NHL
Immunoblastic lymphoma declining less Burkitt’s Lymphoma ?not declining
Treatment of NHL is improving rapidlyNo longer universally fatalAim to treat HIV (HAART) and NHL (chemotherapy) at the same time if at all possible
An unanswered question: what causes NHL?An unanswered question: what causes NHL?
Why has the incidence of NHL increased rapidly in the developed world over the last 50 years?
What is the role of EBV in the non immune-deficient population?
What is the role of immune deficiency?Could a mild, sub-clinical form of immune deficiency explain much of the risk of NHL?
Other immune dysfunctionAuto-immune disease (increased risk)Atopic disease (decreased risk)
Grulich et al, JNCI, 2005Grulich et al, CEBP, 2007
InterLYMPHInterLYMPH– – member studiesmember studies
Next meeting: Sydney July 2008Next meeting: Sydney July 2008
Future directionsFuture directions
Are these cancer-immunity associations reversible? Would earlier therapy of HIV reduce cancer risk? Does cancer risk return to normal on the cessation of immune suppression?Is cancer risk lower among recipients of m-TOR inhibitors?
The role of HPVDoes the wider than expected role of HPV in these settings reflect an important role for HPV in upper aero-digestive cancers in the general population?Should we be vaccinating men?
What explains the increased rate of specific cancers?Lung cancerLip cancerMelanomaThyroid cancer (in ESRD and kidney transplant patients)
Cancer in other conditions of dysregulated immunityPrimary immune deficiency
Is there a highly prevalent but mild form of immune deficiency or immune dysfunction that could explain why NHL has increased so much?
NCHECR, SydneyProfessor John Kaldor
Dr Claire VajdicDr Matthew Law
Yueming LiMarina van Leeuwen
Michael Falster
NSW Cancer CouncilDr Xinan Wan
Professor Bruce ArmstrongDr Anne Kricker
Dr Margaret McCredieAnne-Maree Hughes
Marylon Coates
ANZDATAProf Jeremy ChapmanDr Stephen Macdonald
Dr Angela Webster
St Vincent’s Hospital
Dr Sam Milliken
Dr Jenny Turner
Columbia University, USA
Professor Patrick Moore
Dr Yuan Chang
Viral Epidemiology Laboratory, NCI
Dr Denise Whitby
Interlymph immunology sub-group
Dr Wendy Cozen, UCLA
AcknowledgementsAcknowledgements