Abstract
Age is a major risk factor for many cancers. Although this is usually viewed in the context of the cell biology, we argue here that age-associated changes to immunity may also contribute to the age-associated increasing incidence of most cancers. This is because cancers are immunogenic (at least initially), and the immune system can and does protect against tumorigenesis. However, immune competence tends to decrease with age, a phenomenon loosely termed “immunosenescence,” implying that decreased immunosurveillance against cancer could also contribute to increased disease in the elderly. This review weighs some of the evidence for and against this possibility.
Keywords
1. Introduction
A greatly simplified outline of a common view of tumour immunity suggests that the innate immune system first recognises cancer cells at an early stage of carcinogenesis and the resulting production of IFN-γ triggers an inflammatory cascade that causes limited tumour cell death. Dendritic cells then transport tumour products to the draining lymph node to sensitise the adaptive immune system. The natural immune system meanwhile controls the tumour while CD8+ tumour antigen-specific T cells differentiate in the lymph nodes in concert with CD4-mediated help. Tumour antigen-specific CD8 T cells then infiltrate the tumour and destroy target cells expressing the appropriate antigens.
[1]
This view is still open to question because although there is much evidence that cancers are immunogenic, and many tumour antigens have been identified, the conclusion that the immune system can target these antigens to protect against tumorigenesis is only weakly supported by evidence from clinical trials in humans, and even data from mouse models can be controversial.[2]
There is also a school of thought that immune responses against tumour antigens may even be pro-tumorigenic, a phenomenon described many years ago and termed “immunopotentiation”; a modern incarnation of this idea is the notion that tumorigenesis is enhanced by inflammatory responses.3
, 4
These opposing views may be reconciled by the simple notion that immunity against cancer is a two-edged sword mediating both activities simultaneously.[5]
Nonetheless, there is abundant evidence, beginning with experiments in rats dating back more than half a century, that once tumours are established, they and their products can be recognised by the adaptive immune system and the tumours rejected, with establishment of immunological memory.[6]
Countless experiments since then have confirmed this idea; a recent elegant demonstration in mouse models documented that the great delay in tumorigenesis observed in animals treated with low doses of carcinogens (and therefore likely to be paralleling the development of many human tumours) is mediated by immune surveillance.[7]
This also emphasizes the idea that the tumour co-evolves with immunity, and that the dynamics of this co-evolution are reflected in the divergent results seen at different times in different models, and the great heterogeneity of observations made in clinical oncology. Therefore, a crucial issue is the maintenance of the balance between effective anti-tumour immunity and tumour escape and/or stimulatory mechanisms. “Spontaneous” tumours are likely to have co-existed with immune defence systems over extended periods of time and to have interacted chronically with anti-tumour T cells. This can result in the immune selection of tumour variants no longer recognised by the T cells (recently dubbed “immunoediting”) but also in a situation of “chronic antigenic stress” that can result in the T cell “exhaustion” similar to that seen in persistent viral infections in mice and humans. This type of decreased responsiveness has shown itself to be amenable to modulation by altering the cytokine milieu and/or by influencing signal-transducing receptors and coreceptors on the T cell surface, raising the encouraging possibility that similar approaches might also be successful in cancer.[8]
However, even if this did work in human cancer, whether it would be effective in the elderly in the face of the age-associated immune alterations loosely termed “immunosenescence” is questionable. This is particularly pertinent when we consider that certain immunotherapeutic regimens, also including costimulator manipulation, which are successful in treating cancer in young mice, have been shown to be ineffective in old animals. Therefore, we need to greatly improve our understanding of the likely complex relationships between immunity and cancer in the ageing patient in order to develop therapies appropriate to an “immunosenescent” state.[9]
With the recently increasing realisation that “conventional” anti-cancer therapies such as radiotherapy and even surgery are possibly fully effective only in immunocompetent individuals[10]
this issue becomes urgent not merely for the “niche” immunotherapies of cancer but essentially for all cancer treatments.2. Cancer immunogenicity and immune exhaustion
It is incontrovertible that tumour cells express antigens that can be recognised by the host immune system, at least prior to the end-stage of disease. Numerous reviews have described the categories of antigens that have been identified, and these will not be reiterated here. In some cases, vaccination of patients with these antigens has resulted in clinically beneficial effects, but these are few and far between.
11
, 12
, 13
Considering that many cancer patients are relatively advanced in years, it is justifiable to ask whether some aspect of immunosenescence is responsible, at least in part, for this poor clinical outcome. The “immunological” age (i.e. the individual’s immunological history) as well as chronological age, is likely to be one of the many inter-individual differences resulting in different responsiveness to vaccination. It is not surprising that the mostly late-stage cancer patients treated in experimental therapy trials, whose T cells may already show signs of “exhaustion” due to chronic cohabitation with tumour, in addition to other chronic antigenic stresses, do not fare well under such treatment. Obviously, the prerequisites for success in this type of approach are that the immune system is sufficiently intact such that host T cells can respond to the immunising tumour antigen, and then home to the tumour; the antigen must still be expressed by the tumour, and, finally, that host immunity actually damages the tumour rather than stimulating it. All these parameters may be altered in elderly patients.Responses to vaccination require that vaccine antigens must be presented by antigen-presenting cells (APC) in an activatory not tolerogenic manner; tumour-specific CD4+ T cells must be activated as well as CD8+ cytotoxic effectors, which must be capable of differentiation and persistence in the tumour to exert the desired anti-tumour effect. However, in the elderly, essentially all components of immunity are altered compared to the young; APC are no longer quite so effective, and CD4 cells and especially CD8 cells are particularly susceptible to immunosenescence.
[14]
Thus, the number of Langerhans cells in the skin decreases with age, as does the number of peripheral blood dendritic cells (DC) which show decreased levels of toll-like receptor (TLR)-mediated signalling, decreased expression of the important positive costimulatory receptor ligand molecules CD80 and CD86, but increased expression of the PD-L1 ligand which binds the negative costimulatory receptor PD-1, thereby turning T cells off.[15]
It is interesting to note that several of these changes observed in the elderly have also been observed in cancer patients not at such advanced age; therefore, it might be expected that old cancer patients would have even worse DC function, as a result of age on the one hand, and of cancer on the other.[16]
Similarly, alterations at the T cell level observed in the elderly without cancer may be seen in younger people with cancer.[17]
We hypothesise that in both cases, chronic antigenic stress is the culprit, caused by tumour antigens in cancer patients, and exposure to other persistent antigens in the elderly without overt cancer. We and others have now accumulated a large body of evidence that the persistent antigens causing CD8 T cell exhaustion in elderly people are predominantly derived from the herpesvirus Cytomegalovirus (CMV) for reasons which remain obscure (the persistent herpesviruses EBV, VZV and HSV do not have this effect).[18]
In most populations in industrialised countries, rates of CMV infection increase with age,[19]
and cause alterations in the distribution of CD8 T cells subsets which have often been confused with the effects of the ageing process itself.[20]
Our recent data and those of others suggest that these “age-associated” changes are exacerbated by CMV and do not occur or occur to a much lesser degree in the minority of elderly people remaining uninfected with CMV.[21]
We may therefore ask whether chronic antigenic stress due to exposure to CMV antigens and cancer antigens results in similar changes to immunity due to similar mechanisms. Distinguishing changes caused by CMV from those caused by cancer itself is an important goal. Whether we can modulate immunity in the same way in both cases is a crucial question to answer. One possible model to investigate such manipulations in humans would be to develop an in vitro system in which different agents could be tested.In addition to an “exhausted” T-cell- and reduced APC-function, there is an alteration in the suppressive mechanisms in the elderly. One of the usual suspects in tumour-induced immune suppression are the CD4+ regulatory T-cells (Tregs).
[22]
Different studies document an increase in the frequency of this subset (defined as CD4+CD25hi or CD4+Foxp3+) in the elderly.23
, 24
, 25
, 26
As far as their suppressive activity is concerned, the literature is not as consistent; whereas some studies demonstrate an equal suppressive activity of these cells in young and old individuals,23
, 24
, 27
others report a decreased suppressive activity of this population in the elderly.[28]
This controversy might be due to methodological differences or the differences in age and inclusion criteria of the cohorts studied. However, increased frequency of these cells in the elderly, will most probably contribute to peripheral tolerance to different cancers. Myeloid-derived suppressor cells (MDSCs) comprise another suppressive population, which play an important role in immunosurveillance against cancer.[29]
Although results from animal models suggest an increased proportion of this population in the aged animals,30
, 31
, 32
similar data are lacking in humans.The following sections consider some of the questions raised above, namely whether animal models of immunotherapy support the hypothesis that immunosenescence is important for the outcome of cancer vaccination, and whether there is evidence for the impact of immunosenescence and chronic antigenic stress in human studies, mostly limited to in vitro experiments and sparse observations on patients.
3. Animal models for the effects of age on cancer vaccination
There are now several different immunotherapy models specifically examining the effect of host age on the outcome of treatment. The first of these focussed on gene-therapy experiments involving vaccination of mice with tumour cells transfected with cytokines such as IL 2. These were the first studies to demonstrate that optimising immunotherapy protocols in young mice did not necessarily imply optimisation also for old animals otherwise treated under the same conditions.
[33]
In later studies, summarised and discussed in Ref. [34]
, others showed that old animals’ responses to DNA vaccines encoding tumour antigens were weaker than the young, and that old mice were compromised in their ability to mount an effective antitumour immune response in a breast cancer model; however, compromised function at the antigen presenting level may be overcome by manipulating the costimulatory and/or cytokine environment, or where CD40L proteins modified to include only the extracellular domains are effective in reconstituting responsiveness in older animals. The immune deficit in old mice can also be overcome by targeting costimulation, together with reducing immune suppression and enhancing adjuvant effects using TLR agonists. Here, using a spontaneous breast cancer model, it was found that only combined treatments cured old mice, but with high toxicity and treatment-associated deaths. In these several different animal models, immunotherapy could be successful, but always at greater cost in older individuals.[34]
Thus, age-associated alterations to the crucial antigen-presenting cells, the DCs, reviewed recently in this journal[35]
may represent one of the problems of initiating such responses in the elderly.36
, 37
Nonetheless, even when successful in young animals, this approach may not yield the same results in older animals.[38]
Further adjustment of the therapeutic protocols, such as the use of adjuvants and IL-12[38]
or modification of CD40L may overcome this decreased activity, and be more effective in older animals.[39]
The studies mentioned above mostly employed animal models of established but not spontaneous tumours. A model somewhat more appropriate for human cancer would be to examine the effects of age on immunotherapy of spontaneous tumours, such as the Her2/neu transgenic tumour-tolerant model employed by Lustgarten et al. These investigators attempted to circumvent immune dysfunction in old mice by simultaneously increasing costimulation, decreasing immune suppression and amplifying responses using TLR agonists as adjuvants. These treatments were effective separately in young animals, but needed to be combined to cure old animals. When this was done, the side effects, not seen to such a degree in young animals, were very severe.[40]
Should humans behave in a similar manner to the different murine models described above, then it is likely that elderly and younger patients will respond differently to immunotherapy. This implies that more interventions will be required to achieve an effective response in the elderly, and that great care will need to be exercised to avoid side effects that would not necessarily be problematic in younger patients. Thus, optimisation of vaccines needs to be undertaken specifically for older individuals, and although this is probably feasible, it will be challenging.4. Human immunosenescence
As far as we are aware, there are no clinical cancer vaccination studies published yet in which younger and older patients’ responses have been systematically compared. There are sporadic reports of immunosenescent-like changes in T cells in cancer patients, which may be modelled in vitro. Cloned human T cells can be maintained long-term in culture provided that they are intermittently stimulated via their T cell receptors in the presence of growth factors. They are thus good models for studying the consequences of chronic exposure to a persistent antigen source like a tumour. Growth curves of T cell clones are fairly constant, indicating rigorous clonal expansion, resulting in prolonged T cell responses modelling those to persistent pathogens and cancer. However, culture age-associated changes can be observed in these clones, culminating in the eventual loss of the clone through clonal attrition by apoptosis, i.e. like all normal somatic cells, T cells also manifest a finite lifespan.
[41]
A similar process is likely to occur in vivo, where changes prior to clonal deletion have been termed clonal exhaustion. The best-studied example in humans in this regard concerns infectious mononucleosis caused by primary infection with the persisting herpesvirus EBV. At resolution of the acute phase, there has been a marked expansion of a limited number of EBV-specific clones, only a fraction of which are still found after extended periods, the others having been lost.[42]
This suggests that also in vivo, clonal expansion and exhaustion accompanied by clonal deletion may occur, as illustrated by decreasing telomere lengths in EBV-specific T cell clones in these patients and loss of clones over periods of up to 14 years.[43]
In longitudinal studies of the very elderly, in which we defined an “immune risk profile” (IRP) correlating with 2, 4 and 6 year mortality, an increase in the number of clonal expansions specific for a different herpesvirus, CMV, was found to be a part of the risk phenotype. Infection with EBV, in contrast, was not part of the IRP. However, at the very end of life, the number of such clonal expansions decreased (clonal attrition) and an inverse relationship between their number and continued survival of the subject was found.[44]
Therefore, we suggest that in vitro models of T cell clonal expansion and attrition may be useful in understanding and manipulating potentially similar and clinically important phenomena in vivo. The model is also useful to identify human biomarkers of immunosenescence in vitro at the genetic, proteomic and functional levels, and to seek these in vivo in patients.- Hadrup S.R.
- Strindhall J.
- Kollgaard T.
- Seremet T.
- Johansson B.
- Pawelec G.
- et al.
Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.
J Immunol. 2006; 176: 2645-2653
45
, 46
Thus, we are studying the phenotypes and functions of T cells found in cancer patients in this context. Earlier data suggested the presence of accumulations of dysfunctional T cells with an immunosenescent phenotype in renal cancer (RCC) patients.[47]
RCC is thought to be one of the more immunogenic tumours, according to data on TIL, spontaneous remissions and the clinical experience of response to immunotherapy. If so, it might be more sensitive to any deleterious effects of immunosenescence in the patient. Studies on the peripheral blood and in TIL in these patients occasionally reveal marked accumulations of potentially tumour antigen-specific T cells at levels like those seen for CMV-specific cells in the elderly, i.e. up 10% or more of all CD8 cells.[47]
These accumulated T cells represented oligoclonal expansions possessing a highly differentiated phenotype, and were anergic to peptide-specific stimulation. T cells with a similar phenotype were also present in TIL, suggesting that their dysfunctional status might be contributing to a lack of rejection of the tumour.[48]
5. Regulatory T cells in cancer and ageing
There is a body of evidence that the regulatory elements of the immune system have important roles in the response following cancer cell recognition.
[22]
The regulatory T cells (Tregs) are defined as CD4+CD25highCD127lowFoxP3+. Other cells may share immunosuppressive or regulatory functions, such as CD8+CD103+ or IL-17-producing T cells but more investigations are required to confirm their role. Thus, Tregs present inside the tumour, directly (cell-cell contact) and indirectly (secreted factors) influence the tumour microenvironment. The opposite is also true, i.e. tumour cells also influence tumour infiltrating lymphocytes including regulatory T cells. Moreover, evidence suggests that cells entering the tumour site may become FoxP3+ via TGF-β-dependent mechanisms and thus display regulatory functions.49
, 50
, 51
It is of note that a significant proportion of T cells inside the tumour are indeed tumour antigen-specific.[52]
This suggests that TILs are chronically activated by tumour antigens and start to express markers such as PD-1 with inhibitory signalling responsible in part for the decreased responsiveness and recently associated with poor clinical outcome[53]
while others find a positive correlation between PD-1 expression by regulatory TILs and survival.[54]
Although the important role of Tregs in host immunity is well recognised, as mentioned above, there is very little information concerning their alterations during human aging. Moreover, the available data are controversial[55]
and this lack of information on immune regulatory mechanisms with aging which may be involved in cancer escape is critical. The above-mentioned increased frequency of Tregs inside the tumour strongly suggests that their chronic activation probably induces a “chronic low-grade anti-inflammatory environment” which could counterbalance the age-associated low-grade inflammation commonly prevailing systemically. Further studies will be required to test Treg frequency and functions in the periphery and inside the tumor, and the impact of the hypoxic environment thereon, an important point given the frequently low oxygen within tumours. Furthermore, models for chronic activation of Treg should be developed and should take into account artifacts of the in vitro culture conditions usually employed for such assays (i.e. culture in air).6. Hypoxia in cancer and in culture models
An important variable parameter which is specific to the tumour microenvironment is the oxygen level. Dysregulated angiogenesis within the tumour creates a hypoxic environment, which may be too harsh for T cells to function properly and exert their effector role. In this respect, aged or exhausted T cells may respond differently to lower oxygen environments. The expression of hypoxia-inducing factor-1 (HIF-1α) under low oxygen was recently shown to be inhibitory for T cell activation and to decrease inflammation, consistent with this hypothesis. Moreover, recent data suggest that T cells have a propensity to differentiate into regulatory T cells under lower oxygen level and that regulatory T cells grown under these conditions display significantly higher suppressor activity compare to cells grown in air. Molecular data showed that HIF-1α upregulates FoxP3 expression in human T cells
[56]
and for this reason we can conclude that tumors control the surrounding inflammatory level via hypoxia and shut down immunity by expression of HIF-1α which inhibits T cell functions and leads to increased numbers and suppressive properties of Tregs. Thus, one should be aware that the data discussed in this review, which include in vitro data gathered from work using cultures in air should be carefully and critically interpreted according to changing cellular functions depending on the oxygen level.7. Additive effects of chronic antigenic stress?
If both tumour antigens and viral antigens appear to drive T cells towards senescence, we may ask whether there is any evidence in favour of an additive effect of different sources of chronic antigenic stress on T cell function. Specifically in this context, does CMV infection exacerbate dysfunctional immune status in cancer patients? Very few attempts have been made thus far to answer this question. In one published study, Chen et al. proposed that the immune impairment seen in cancer patients, while associated with multiple factors such as the stage of cancer and impact of treatment schedules, was also a consequence of CMV infection.
[57]
However, because the fraction of the population infected with CMV increases with age, plateauing only at 75–80 years, age-associated immune alterations in cancer patients might also be linked to age-associated increases in CMV infection.[58]
However, this is also an area where there are very few data available, and those that are available tend to be controversial. Nonetheless, and despite the high prevalence of CMV in most elderly populations, there have been some sporadic reports on worse outcomes in cancer patients who are CMV+ compared with those not infected, or that certain cancers are much less common in CMV-negative people. For example, Herne et al. reported that CMV seropositivity was strongly associated with mycosis fungoides and Sezary Syndrome, even in the earliest stages, and was significantly higher than in either healthy or even immunocompromised controls.[59]
However, other investigators did not find this association in their patients.[60]
Some associations with cervical cancer have been noted.[61]
However, as Chan et al. put it, “The ubiquitous nature of herpesviruses may pose difficulty in elucidating their pathogenic role. These results indicate that CMV, HHV-6, and HHV-7 are bystanders rather than cofactors in the oncogenesis of cervical cancer.”[62]
Nonetheless, a recent report has suggested that in breast cancer, HSV-1, HHV-8, EBV, CMV, and HPV were all related to overall survival, although only HHV-8 and CMV were relevant regarding relapse-free survival.[63]
This latter finding is consistent with an earlier proposal that CMV could be a risk factor for breast cancer.[64]
8. Concluding remarks
Here, we have argued that cancers are intrinsically immunogenic and as such can be recognised and, theoretically, rejected by the host immune system, but that clinical immunotherapy protocols require optimisation for use in older individuals. Of the many possible reasons for differences between younger and older patients, we further argue that especially clonal T cell immunity to persistent antigens, such as cancer antigens, becomes exhausted over a long period of exposure. Initially clonally heterogeneous responses maintain immunosurveillance, but as time goes by, oligoclonal accumulations of dysfunctional cells appear, followed by repertoire shrinkage (reduction in the number of different clones present) and eventual clonal deletion of the antigen-specific cells and loss of immunity. The final result of these changes both in cancer patients and in the elderly due to CMV infection is predicted to be a kind of immunodeficiency for novel antigenic challenges as well as loss of responsiveness to the persistent antigens themselves. Thus, general and specific immunodeficiency would both contribute to morbidity and mortality in cancer patients and the elderly. The question remains open as to whether CMV infection and cancer together result in a more rapid deterioration of immunity contributing to infections and morbidity in cancer patients. This “vicious circle” would involve more frequent CMV reactivation due to both immune attrition and chemotherapy and result in even more accelerated deterioration. A study on the small minority of elderly patients who remain CMV-negative would help answer some of these questions.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
The Tübingen Ageing and Tumour Immunology Group is currently supported by the Deutsche Forschungsgemeinschaft (DFG PA 361/11-1; PA361/14-1), the European Commission ((EU-LSHG-CT-2007-036894 “LifeSpan”) and the University of Tübingen Clinical School fortüne grant #1732-0-0. This paper is based on a presentation delivered at the 9th SIOG Conference, Montreal, 18 October 2008.
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Biography
Graham Pawelec, PhD received an MA in natural sciences in 1978 and a Ph.D. in transplantation immunology in 1982 from the University of Cambridge, and the Dr. Habil and Venia Legendi from the University of Tübingen, Germany, where he became a professor of experimental immunology in 1997. He is affiliated to the Center for Medical Research, University of Tuebingen Medical School (2nd Department of Internal Medicine). He is a visiting professor, Nottingham Trent University, UK, and member of the Sanofi-Pasteur-MSD and Sanofi-Aventis Advisory Boards on Immunosenescence and Vaccination, and of the WHO Initiative for Vaccine Research Advisory Board on the Impact of Ageing on Vaccination. He is Co-Editor-in-Chief of Cancer Immunology Immunotherapy and is on the editorial boards of Immunity & Ageing, Mechanisms of Ageing & Development, Experimental Gerontology, Biogerontology and the Journal of Translational Medicine. He has coordinated three European Union collaborative programs on immunosenescence (EUCAMBIS, ImAginE and T-CIA) and two on cancer vaccine research (EUCAPS and ESTDAB). His research interests currently centre on alterations to immunity, especially T cell-mediated immunity, in ageing and cancer in man and the influence these have on the outcome of vaccination. He is working on mechanisms of human immunosenescence and the initially unexpected and surprising discovery of the impact of infection with the common herpesvirus Cytomegalovirus on immunity and mortality in the elderly. The impact of polypathogenicity (including multiple infections, cancer, Alzheimer’s, autoimmunity) as well as stress (psychological, nutritional) on immune signatures reflecting individual immune status is of particular interest in the clinical context.
Article info
Publication history
Accepted:
April 6,
2010
Received:
April 5,
2010
Identification
Copyright
© 2010 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
