Article Published in the Author Account of

Tamas Fulop

Aging, Immunity, and Cancer

Abstract: Age is the most important risk factor for tumorigenesis. More than 60% of new cancers and more than 70% of cancer deaths occur in elderly subjects >65 years. The immune system plays an important role in the battle of the host against cancer development. Deleterious alterations occur to the immune response with aging, termed immunosenescence. It is tempting to speculate that this waning immune response contributes to the higher incidence of cancer, but robust data on this important topic are few and far between. This review is devoted to discussing state of the art knowledge on the relationship between immunosenescence and cancer. Emerging understanding of the aging process at the molecular level is viewed from the perspective of this increased tumorigenesis. We also consider some of the most recent means to intervene in the modulation of immunosenescence to increase the ability of the immune system to fight against tumors. Future research will unravel new aspects of the immune response against tumors which will be modulable to decrease the burden of cancer in elderly individuals.



Introduction

Most types of cancer can be considered age-associated diseases (Anisimov, 2009; Franceschi and La Vecchia, 2001; Burkle et al., 2007), suggesting close relationships between mechanisms controlling aging and cancer (Pawelec and Solana, 2008; Campisi and Yaswen, 2009). More than 60% of new cancers and more than 70% of cancer deaths occur in elderly subjects >65 years; however, this tendency stops at 90 years and seems to plateau (Yancik and Ries, 2004). Thus, the cancer/age relationship is complex and not yet well understood. Many lines of evidence point to the most important factor simply being the passage of time (Anisimov, 2009), allowing the accumulation of damage from free radicals, viruses, or carcinogens, or other agents causing mutations favoring the development of cancer (Federico et al., 2007). Not only are oncogenes more active, but the “gatekeepers” of the genome, such as p53, can themselves be damaged and become less efficient in eliminating damaged cells (Salvioli et al., 2009). Moreover, epigenetic changes including DNA methylation, histone-modifying complexes, and glycosylation, which play an important role in the aging process, also impact either directly (Jones, 2005; Rodriguez-Rodero et al., 2010; Agrawal et al., 2010) or via epigenetic alterations in immune cell functions (Fernandez-Morera et al., 2010) on age-related carcinogenesis (Figure 1).

Figure 1. Causes of increased cancer incidence with age.

Figure 1. Causes of increased cancer incidence with age.

There are well-known alterations occurring in the immune response with aging affecting both innate and adaptive immunity (Table 1), generally viewed as detrimental and designated “immunosenescence” (Fulop et al., 2007; Larbi et al., 2008). Nevertheless, their contribution to the development and progression of cancer, and implications for its treatment in elderly people, are controversial (Malaguarnera et al., 2001; 2010; Derhovanessian et al., 2008). It has long been accepted that aging is accompanied by a low grade inflammation (Miki et al., 2008; Vasto et al., 2009) which appears to play a role both in the process of aging and in the pathogenesis of several age-related diseases, possibly including cancer (Candore et al., 2010; Khatami, 2009; Ahmad, 2009). Additionally, many other factors favoring cancer development, such as apoptosis resistance, replicative senescence, microenvironmental imbalance, chromosomal instability, hypoxia, and decrease of immunosurveillance, all become more prevalent as part of the aging process (Zitvogel et al., 2006; Allen and Jones, 2011).

What Are the Main Changes Seen in Immunosenescence?

Adaptive immunity

Immunosenescence, by definition reflecting the erosion of immune competence (Larbi et al., 2008; Ostan et al., 2008; Pawelec and Larbi, 2008), particularly affects the T cell compartment of adaptive immunity, but also causes measurable changes in other arms of the immune system (Ostan et al., 2008). The most clearly observed and often-reported robust differences between the young and old people in the T cell compartment are (i) at the single cell level, functional differences are recorded, particularly in receptor signal transduction pathways (Larbi et al., 2011); (ii) at the cell population level, differences in cell distribution are seen, especially the lower percentages of naïve CD8+ T cells within the CD3+ peripheral blood population, and in some reports, also naïve CD4+ cells (but never as marked as the CD8+ T cells); reciprocally, there is a higher frequency of memory CD8+ T cells, and possibly also an increase in absolute numbers especially in the very elderly, again with a lesser effect on CD4+ cells (Fagnoni et al., 2000; Saule et al., 2006; Henson and Akbar, 2010; Nikolich-Zugich and Rudd, 2010); and (iii) as a result of these two main types of change, differences at the functional level may read out as a shift toward a T helper 2 (Th2) phenotype and the production of higher amounts of Th2 cytokines such as IL-4, IL-5, and IL-13 (Rink et al., 1998), and with less IL-2 produced, less cell proliferation (T cell clonal expansion) and greater apoptosis resistance. The reduced availability of naïve cells and other changes are thought to explain the reduced ability of the elderly to respond to new antigens (although this remains a hypothesis in humans), while their accumulated memory cells may also acquire dysfunctionality, even to the point of mediating immunosuppressive activities.

It is not only T cells that are affected in aging, but accumulating evidence points to intrinsic functional as well as phenotypical changes in B cells (Frasca et al., 2011). The most significant changes include decreased repertoire diversity, which has also been documented to a limited extent at least in CD4+ T cells. As with T cell, decreased cell activation through the B-cell antigen receptor has been reported. This leads to decreased production of antibodies with lower titer and affinity; equivalent changes to receptor properties have not been seen in T cells (Dunn-Walters and Ademokun, 2010). There is also evidence for the accumulation of functionally exhausted memory B cells with aging (Bancos and Phipps, 2010) with concomitant decrease in naïve B cells, again similar to T cells. These differences would be expected to impact on immune competence.

The causes of these differences between younger and older people in the adaptive immune response are not well understood. While most data in humans are derived from cross-sectional studies, one should view the differences observed between groups with caution. However, animal models, mostly mice, and very limited longitudinal studies in humans, do suggest changes within individuals over time. Three main reasons for these may be suggested: (i) thymic involution resulting in drastically reduced output of naïve T cells (Mitchell et al., 2006), (ii) changes to cell membrane composition and/or damage resulting in altered signaling (Larbi et al., 2006; 2011), and (iii) immunological history, i.e., the onslaught of antigenic stimulation throughout life (pathogens, parasites, possibly cancer) which eventually may result in “immune exhaustion” (Pawelec et al., 2009). Thus, persistent stimulation will have many sources, for example (i) from a viral source such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV), (ii) from other persistent pathogens such as parasites, (iii) from tumor antigens, and (iv) from cell intrinsic sources (De Martinis et al., 2005). This may also contribute to the heightened background inflammatory state often recorded in the elderly and dubbed “inflamm-aging.” Eventually, this impacts on the development of age-associated chronic diseases such as atherosclerosis, diabetes, Alzheimer’s disease, and possibly also cancer (Figure 2).

Figure 2. Leading causes of compromised immunosurveillance in the elderly.

Figure 2. Leading causes of compromised immunosurveillance in the elderly.

There is now accumulating evidence suggesting that whether a person manifests an “immunosenescent” immune profile depends on their seropositivity to the persistent herpesvirus CMV (Pawelec et al., 2009a; Faist et al., 2010; Moss, 2010; Limaye and Boeckh, 2010). The decrease in naïve:memory CD8 cell ratio is marked only in CMV-infected people, and then only in a minority of them. As the frequency of CMV infection increases with age, this parallels age-associated change (Looney et al., 1999), but is caused by viral infection, not aging. The accumulating memory cells bear markers of late-differentiated cells characterized by the expression of the surface markers CD45RA, CD57, and KLRG-1, but absence of CCR7, CD28, and CD27. Even in those individuals with greater retention of thymic function in later life, there is the belief that the finite “immunological space” is already filled with these late-differentiated cells and T cell homeostasis will prevent access of more naïve cells to the periphery (Franceschi et al., 2000a). More recent data, however, challenge this assumption and suggest that the “immunological space” may be more flexible than previously appreciated, at least in mice (Vezys et al., 2009).

The two longitudinal studies of free-living elderly people in Sweden (Wikby et al., 2002; Olsson et al., 2000) sought to identify immune markers correlating prospectively with 2-, 4-, and 6-year survival. These studies defined a cluster of parameters which included CMV-seropositivity, and increases in the absolute numbers as well as percentages of late-differentiated CD8 cells of the type known to be stimulated by CMV infection. This resulted in the emergence of the hallmark characteristics of the so-called “Immune Risk Profile” (IRP) (Derhovanessian et al., 2009), i.e., an inverted CD4:8 ratio, poor overall T cell proliferative responses, and expansion of the CD8+CD28-negative compartment. These markers are all influenced by CMV infection, which is thus demonstrated to exert a major impact on age-associated changes (longitudinal studies on the same individuals) which do contribute to a robust and objective, albeit rather crude, clinical outcome, namely mortality. Clearly, CMV alone is not responsible for this, because 85% of individuals not assigned to the IRP were nonetheless CMV-infected, as against 100% of those in the IRP group. It is very likely that, in addition to an environmental component influencing these events, there is a strong genetic background mediating resistance to the detrimental effects of CMV (Derhovanessian et al., 2010).

As mentioned above, it is not only alterations to the proportions of naïve and memory cells that seem to change with age (and CMV infection), but also changes to functional integrity on a per-cell basis which might reflect genuine “aging” effects rather than pathogen exposure. Thus, decreased signal transduction capacity of T cell surface receptors such as T cell receptor (TCR), CD28, or cytokines may greatly affect immune competence (Larbi et al., 2011). This manifests as decreases in the phosphorylation cascade following receptor ligation, from the membrane to the nucleus (e.g., NF-κB, NFAT). Altered activation of tyrosine kinases such as Lck and Fyn and altered phosphorylation of adaptor molecules such as LAT or SLP76 are responsible for the overall reduced T cell signaling with aging (Larbi et al., 2006). Recently, dysregulation of kinase and phosphatase activities was found with excess inhibitory activity of phosphatases such as SHP-1 and PTEN (manuscript in preparation). These alterations originate from changes in the physico-chemical properties of the membrane leading to malfunctions of lipid raft assembly and functions in the membrane (Fulop et al., 2006).

These numerous age-associated alterations at the phenotypical and functional levels in the adaptive immune system are hallmarks of immunosenescence assumed to be likely to contribute to many age-related diseases such as infections, neurodegenerative diseases, and cancer.

Innate immunity

Not only is the adaptive immune response altered, but it has also recently become evident that most innate immune functions are affected at least to some extent by the aging process (Panda et al., 2009; Alper, 2010; Shaw et al., 2010). Neutrophils are generally the first cells to arrive at sites of damage, but in the elderly these cells have decreased chemotactic and phagocytic activities and lower free radical-producing capacity (Fortin et al., 2008) mostly due to altered signal transduction through specific surface receptors such as Toll-like receptor (TLR) and granulocyte/macrophage colony-stimulating factor (GM-CSF) (Fulop et al., 2004; Wessels et al., 2010). The number of natural killer (NK) cells (mainly CD56dim) increases, while those with CD56bright decreases with aging (Krishnaraj, 1997). There are also discrete alterations in NK cell functions with aging, such as IL-2 production and cytotoxicity on a per cell basis (Mocchegiani et al., 2004). Furthermore, many cytokines and chemokines produced by NK cells are decreased with aging, such as IL-8, IFN-γ, and others (Mocchegiani et al., 2009).

Dendritic cells (DCs) seem also to be altered not only in their basic functions such as phagocytosis, chemotaxis, and production of IL-12, but also in their ability to activate naïve CD4+ T cells via antigen presentation (Agrawal et Gupta, 2010; Della Bella et al., 2007; Panda et al., 2010) while their number and phenotype do not change (Agrawal et al., 2007; Jing et al., 2009). DCs have reduced antigen processing capacity concomitantly with the altered expression and function of their co-stimulatory molecules, although they seem to retain the capacity to produce pro-inflammatory cytokines and to activate CD8+ T cells (Agrawal et al., 2008). Furthermore, IFN-α production was found to be decreased in plasmacytoid DCs (Panda et al., 2010). These functional changes are related to altered expression and signaling of various so-called “Pattern recognition receptors” such as TLRs, NOD, RIG-like receptors, and C-type lectin receptors (Agrawal et al., 2010). The most important changes are in the decreased PI3K signaling pathways influencing the TLR signaling (Agrawal et al., 2007). Monocytes or macrophages, which are important in recognition and clearance of invaders through their TLRs, are also impaired with aging (Dace and Apte, 2008; Gomez et al., 2008) leading to altered cytokine secretion (van Duin et al., 2007), and effector functions (Agius et al., 2009).

Taken together, the age-associated changes in each of the cell types categorized as parts of the innate immune system are likely to have direct effects on immune competence, as well as contributing to the altered adaptive response and to the maintenance of low grade inflammation in aging.

Low grade inflammation: inflamm-aging

As alluded to above, an apparent disequilibrium between the retention of a relatively reactive mainly pro-inflammatory innate immune response with aging and the more severely altered adaptive immune response leads to the presence of a low grade inflammatory status commonly present in the elderly (Franceschi et al., 2000b), although the cause of this is certainly multifactorial. It is likely that one of the most important causes is chronic antigenic stimulation. The antigen source can be exogenous, as with CMV mentioned above, but also including bacteria and other viruses, or endogenous like the various post-translationally-modified macromolecules such as DNA or proteins which can be modified by oxidation, acylation, or glycosylation. Such altered molecules can stimulate the innate immune response, particularly macrophages via TLRs, thus contributing to sustaining a pro-inflammatory state. This is measurable in some circumstances such as increased circulating levels of IL-6, IL-1β, or TNFα.

Thus, a chronic low grade inflammatory process accompanies aging and this may be the cost for maintaining immune surveillance against persistent pathogens or endogenous stressors such as cancer cells. All these changes contribute to a decreasingly effective immune environment unable to respond appropriately to new antigens such as represented by the continuous emergence of tumor cells during the human lifespan.

Does the Immune Response Play a Role in Cancer Development and Surveillance?

Figure 3. Breaking the equilibrium that prevents cancer initiation and development.

Figure 3. Breaking the equilibrium that prevents cancer initiation and development.

Classically, cancer immunosurveillance is defined as the ability of the immune system to limit tumorigenesis and prevent spread by recognizing modified self cancer antigens and eliminating or otherwise controlling cancer cells. Efficient immunosurveillance would obviously require cancerous cells to be eliminated or their proliferation blocked before they can develop into a clinically recognizable tumor. It is now increasingly clear from animal models that innate immune responses are involved as a first line of defense against nascent tumors, after which adaptive immunity may be triggered to prevent cancer recurrence. This is assumed to apply to humans as well. A current model of immunosurveillance proposes that immunoselection must operate in the face of immunosubversion and that the dynamic of these two opposing processes dictates disease course and final outcome (Zitvogel et al., 2006). However, these two processes are in reality likely to be a continuum, whereby multistep carcinogenesis results from cross-talk of cancer cell intrinsic factors and the host immune system (cell extrinsic effects) capable of both preventing and facilitating carcinogenesis (Zitvogel et al., 2006; Swann and Smyth, 2007). According to this view, the appearance of pre-malignant lesions signals a stage where the immune system has lost the ability to block nascent cancer. This stage thus corresponds to the loss of proper functional preventive immunosurveillance by both innate and adaptive immunity against “stress signals” such as those caused by DNA damage or necrotic debris or the microenvironment, and including modified self antigens generated by virtue of genetic instability or chromosomal fusions within the cancer cells (Figure 3). At this stage, the immune system must deal with an established tumor, akin to having to deal with a persistent infection, and reflecting the same processes of immune selection and evasion as seen in infections of this type. Thus, during advancing oncogenesis, immunoselection of the target cancer cells will occur, which can be balanced by the appearance of cell variants to maintain a state of equilibrium. This results in an equilibrium between the developing tumor and the anti-tumor immune response, as a consequence of the incomplete elimination of tumor cells during the earlier phase (Figure 3). The immune system must exert powerful selective pressures on the tumor cells which will evolve variants able to resist the immune response. The final stage of tumor growth thus unfortunately often culminates in immunosubversion (tumor escape) which can even exploit the immune system to even favor tumor growth (Zitvogel et al., 2006). This often involves several of the many mechanisms by which tumors actively suppress immune responses by producing different inhibitory substances, e.g., NO, IDO, PGE2, IL-10, and TGF-β.

Together, these multiple findings suggest that at the beginning the immune system plays an essential role in tumor elimination (but at the same time may also be involved in tumor formation, a true double-edged sword), involving many players such as CD8 cytotoxic T cells, Th1 responses, NK cells, macrophages, B cells, and γδ T cells. It is therefore likely that a compromised immune system, either because of acquired immune tolerance or because of the intrinsic changes that may occur during aging, may favor tumor development and progression (Table 2), rather than immune control. This might be balanced in later life by a weaker pro-tumorigenic action of immunity, possibly partly explaining why the very elderly suffer less from de novo carcinogenesis than younger people.

Interactions of the different players

As already mentioned one other important factor contributing to the development of cancer is the low grade inflammation occurring with aging (Franceschi et al., 2000b). This arises from the over-production of pro-inflammatory cytokines such as IL-6, TNF, and IL-1 by innate immune cells and is also associated with neuro-endocrine changes such as increased glucocorticoid and decreased insulin growth factor-1 (IGF-1) levels. This continuously ongoing chronic inflammation could further damage cells through the increased production of cytokines and free radicals. On the one hand, the unbalanced cytokine production due to increased pro-inflammatory activity favors neoplastic cell transformation by increasing oncogene expression, survival, angiogenesis, and metastatic spread, and on the other hand the anti-inflammatory cytokines favor immunosuppression, tumour growth, and angiogenesis. Thus, the systemic balance and the tumor micro-environmental balance of cytokines are essential for determining whether they will favor or impair tumor development or progression. In aging, changes to both of these milieus may favor tumor development.

The production of free radicals plays a special role as it contributes to the aging process, although their importance in this context is still questioned. Free radicals are constitutive components of the inflammatory process both inducing it and being induced by it. They may play a beneficial role by converting pro-inflammatory into anti-inflammatory molecules and as such helping to resolve inflammation. In contrast, in a chronic pro-inflammatory state where tissue injury and healing mechanisms are present simultaneously the damaging effect of overproduced free radicals manifests itself slowly but constantly, maintaining the pro-inflammatory status favoring the tumor development and progression. The redox regulation of PTEN activity is a typical example (Covey et al., 2010) which may well occur in the context of the low inflammatory process during aging. In this respect, it was further shown that long-lived animal species have an increased resistance to stress and more readily upregulate downstream components of the cytoprotective nuclear factor erythroid 2-related factor (Nrf2) signaling pathways (Lewis et al., 2010; Martin-Montalvo et al., 2011; Sykiotis et al., 2011). The pro-oxidant-induced Nrf2-signaling pathways mediate multiple avenues of cytoprotection by activating the transcription of more than 200 genes encoding proteins that neutralize and detoxify both endogenous and environmental toxins, and regulate factors important in cell cycle and growth (Lee et al., 2003). Concomitantly, this activation of Nrf2 leads to a decrease in the inflammatory response via repression of multiple pro-inflammatory genes (e.g., TNF-α, IL-1β, IL-6) by antagonizing NF-κB (Kim et al., 2009; Jin et al., 2008). Nrf2 interacts with other important cell regulators such as the tumor suppressor protein 53 (p53) and NF-κB and through their combined interactions protecting against many age-related diseases including cancer. Nrf2 may be a significant component of the activation pathway of p53 which is necessary for eliminating damaged cells. However, the p53 pathway is altered with aging leading to the accumulation of damaged and possibly senescent cells which can further progress to oncogenesis (Salvioli et al., 2009). Thus, we can hypothesize that with aging even in long-lived species the Nrf2 signaling pathway could be altered leading to a chronic inflammatory status and as such favoring the emergence of tumors. However, there are currently no data concerning the expression and activity of Nrf2 in the context of immunosenescence.

Because chronic antigenic stimulation, particularly by CMV, seems to have such an important role in immunosenescence and inflamm-aging, it may also play a role in cancer development. Chronic antigenic stress due to CMV and tumor antigens might be additive and contribute to more rapid immune exhaustion in CMV-positive patients. To the best of our knowledge, this has not been tested yet. The cells accumulating most markedly in the elderly are certainly highly pro-inflammatory and further contribute to the heightened systemic inflammation seen with aging, also causing molecular damage leading to neoplastic transformation (Davalos et al., 2010). This type of putatively senescence-instigated inflammation is referred to as a chronic low level ’sterile’ inflammation (Rodier and Campisi, 2011). Thus, aging facilitates a vicious circle by inducing chronic inflammation leading to specific T cell subsets accumulation, which in turn maintains the inflammatory status potentially exacerbating cancer development.

A role for miRNAs in carcinogenesis is now becoming accepted (Li et al., 2010; Hong et al., 2010; Farazi et al., 2011; Grillari et al., 2010). miRNAs regulate gene expression by inducing translational inhibition and cleavage of their target mRNAs through base-pairing to partially or fully complementary sites (Li et al., 2010). There are numerous pathways by which miRNA participate in tumorigenesis either by directly affecting pathways in cells leading to transformation or progression (Meister and Schmidt, 2010) or by participating in the inflammatory processes facilitating cancer development (Montano and Long, 2010). Some miRNAs can silence PTEN and consequently activate the PI3K-Akt-mTOR pathway leading to tumorigenesis (Olive et al., 2009). There is still much to investigate in relation to immunosenescence, low grade inflammation, cellular signaling, and the role of miRNA networks in aging and age-related diseases such as cancer.

PI3K-Akt-mTOR/FOXO signaling

Similarly, the role of metabolic pathways in immunosenescence and cancer is being actively investigated (Hsu and Mountz, 2010; Evans et al., 2010; Powell and Delgoffe, 2010). PI3K-Akt-mTOR/FOXO signaling plays a central role both in the maintenance and generation of T cells and in tumor progression and anti-cancer drug resistance. PTEN negatively regulates this pathway (Covey et al., 2010), which is also related to the insulin/IGF pathways (Frauwirth et al., 2002). The activation of mTOR can lead to deregulation of cellular metabolism in the direction of uncontrolled T cell differentiation, cell growth, and proliferation. The presence/activation of mTOR favors the development and maintenance of naïve CD4 T cells, while in the absence/inhibition of mTOR naïve CD4 T cells differentiate into Foxp3+ regulatory T cells (Tregs) and CD8+ T cells develop into memory T cells. This is further favored by the loss of CD28 on CD8+ T cells, as well as by hypoxia (Evans et al., 2010; Eltzschig and Carmeliet, 2011). Thus, it is conceivable that with aging there is a dysregulation in the metabolic sensing CD28-PI3K-Akt-mTOR/FOXO signaling pathway supported eventually by a hypoxic microenvironment which skews the T cell response toward the preponderant development of CD8+ memory cells and CD4+ Tregs and induction of a proinflammatory milieu, leading to tumor development, as hallmarks of immunosenescence. It is of note that inside every tumor there persists a highly hypoxic environment, which may have a long-lasting effect on the differentiation of infiltrating lymphocytes. The study of these metabolic pathways is crucial to our understanding of associations between immunosenescence and cancer. To add further to the complexity of the effect of metabolic pathways on immunosenescence, low grade inflammation, and cancer, recently sirtuins were also reported to contribute to reduced cellular activation by decreasing NF-κB and deacetylating FOXO transcription factors (Kyrylenko and Baniahmad, 2010; Donmez and Guarente, 2010). However, their role is still not well understood and more work is needed to elucidate their implications for tumorigenesis via the age-related low grade inflammation.

As we have discussed, specific aspects of immunosenescence could well prevent an effective immune response against cancer and result in the overall age-associated increased susceptibility to cancer. What the exact contribution of each parameter actually is still requires much investigation. Studies of the last few years have nevertheless helped to unravel several important molecular players which may begin to explain associations of immunosenescence with increased development of cancer. However, of the many parameters implicated, distinguishing those that are most important from those that may merely be epiphenomena could optimize treatment in future.

How Does Immunosenescence Impact on Cancer Development and Progression?

Given the plethora of age-associated changes contributing to immunosenescence (both innate and adaptive) the question arises of which, if any, could be responsible for the increased incidence of cancers with aging and why the elderly cannot mount an adequate immune response against an immunogenic tumor. Specific alterations occurring with aging in the innate and adaptive immune responses which contribute more specifically to the development of cancers may be considered as follows.

Given that DCs bridge innate and adaptive immunity, even the subtle age-associated changes observed in these important antigen-presenting cells (APC) might have marked “knock-on” effects. Different expression of co-receptors including B7.1, B7.2, OX40, CD27, CD30, CD40, and 4-IBB, even if marginal, might have an amplified effect in modulating T cell activation (Morel et al., 2001; Sharma et al., 2006). Moreover, DCs influence T cell differentiation following activation, by virtue of their cytokine production which is also altered with age. Thus, DCs may contribute to the altered Th polarization towards the Th2 response and to the maintenance of a low grade inflammation with aging (Agrawal and Gupta, 2011). Moreover, in the context of tumor immunity, the antigen presenting capacity of DCs and their T cell response modulating effect are compromised by inhibitory factors such as PGE2, TGF-β, IL-10, and VEGF secreted by tumor cells which can induce down-regulation of the number of MHC molecules and other important surface moieties. These alterations in DC functions lead to a weakened T cell response to emerging cancers and even to anergy toward them, which could be exacerbated by aging.

Other innate immune cells with direct anti-tumor effects may also be compromised with age. Decreased cytotoxicity against tumor cells has been reported in monocytes from elderly people and neutrophil functional changes may also contribute to tumor progression (Fortin et al., 2008). These changes may be due to altered expression of TLRs and in their functionality through altered signaling in all cells of the innate immune response, contributing generally to low grade inflammation, dysregulation of tissue repair, regeneration, and apoptosis favoring the emergence and progression of tumors with aging (Balistreri et al., 2009; Ioannou and Voulgarelis, 2010).

NK cells play a special role in the age-related increase of cancer as they are major killers of emergent tumor cells. The altered phenotype of NK cells, as well as their decreased cytotoxic activity on per cell basis with aging, is likely to contribute to the increase of cancer with aging. Furthermore, the decreased production of IFN-γ, IL-8, and chemokines probably contributes to decreased functionality as well as altered adaptive immunity.

Aging is also characterized by the emergence of a network of immune suppressive mechanisms including an increased frequency of myeloid-derived suppressor cells (MDSC), indoleamine-2,3-dioxygenase (IDO) production, and B7 family molecule expression (B7-H1). Regulatory T cells (Tregs defined as CD4+CD25+FoxP3+) maintain and induce immune cell tolerance by inhibiting a variety of cells such as T cells, NK cells, and DCs through direct cell-cell contact (Sakaguchi et al., 2008) as well as by means of secreting two Th2 cytokines, IL-10 and TGF-β, which possess immunosuppressive activities. There is increasing evidence that the number of CD4+CD25+FoxP3+ T cells is increased in aged humans (Gregg, 2005; Wang et al., 2010). This could contribute to tolerance towards cancers in elderly subjects by decreasing the cytotoxic activity of CD8+ T cells and NK cells. Furthermore, MDSC are a heterogeneous population comprised of macrophages, neutrophils, and dendritic cells. Interestingly, all these cells are able to suppress the activation of CD4+ and CD8+ T cells and consequently induce the inhibition of the generation of antitumor responses (Nagaraj and Gavrilovich, 2008). Moreover, these cells are specifically activated by different anti-inflammatory factors including IL-10, TGF-β, VEGF, which are known to increase with aging. This suggests that the shift toward an anti-inflammatory response (Th2) or the anti-inflammatory cytokines directly secreted in the tumor environment favor the activation of these MDSC which consequently can suppress the activation of an adequate immune response (Huang et al., 2005). Recently, it was shown by Enioutina et al. (2011) that MDSC-related cells in old mice (Gr1+CD11b+ cells) possess the ability to suppress T cell proliferation/activation and produce heightened levels of pro-inflammatory cytokines through the alteration of the PI3K-Akt signaling pathway. This further contributes to our understanding of how these cells can suppress adequate immune antitumor response with aging. Indoleamine-2,3-dioxygenase (IDO), whose level was also shown to increase with age (Pertovaara et al., 2007), is an immunosuppressive molecule which is able to inhibit T cell activation. Thus, the increased level of IDO with aging further contributes to the decreased immune response to tumors. Recent data showed that the expression of PD-L1 (programmed death ligand 1) is altered with aging but this requires further investigation to better dissect out its role in the age-related emergence of cancers (Agarwal and Gupta, 2010).

Is There Hope of Restoring Appropriate Anti-cancer Immunity in the Elderly?

Truly effective therapy against most cancers at any age is still lacking (Lustgarten, 2009; Pawelec et al., 2009b). Certain therapies can be combined to act at multiple different loci to improve immunity (Gravekamp, 2009a; 2009b). As discussed above, immunosenescence may compromise many potential anti-tumor mechanisms, including tumor antigen presentation, and may result in blockade of immune regulatory checkpoints (Lustgarten, 2010; Palucka et al., 2010). Theoretically, cancer vaccination efficacy could be improved also in the elderly by (i) reducing suppression of T cell activation, (ii) stimulation of cells which kill tumor, (iii) improving DC antigen presentation, (iv) recruitment of naïve T cells by IL-7 (Provinciali, 2009), (v) lifting checkpoint blockade by inhibiting the CTLA-4 (cytotoxic T lymphocyte antigen 4) or PD-1 (programmed death 1) negative costimulatory receptors. Particularly the latter has achieved significant clinical success in treating melanoma patients, as reflected by the recent approval of ipilimumab (anti-CTLA-4) by the FDA. There is hope that with the better understanding of the interactions between immunosenescence and tumorigenesis we can design better vaccines in the elderly to combat cancers. This is now also particularly important in light of the earlier FDA approval of a prostate cancer vaccine/adoptive immunotherapy procedure (Sipuleucel-T, Provenge) which itself showed some interesting age-associated effects in the clinical trials testing the immunotherapy’s efficacy. However, in this case, a greater survival advantage accrued to patients older than the median age, not younger (Kantoff et al., 2010).

In the context of cancer immunotherapy, there is one area where immunosenescence would be expected to make a real difference, namely, in prophylactic vaccination. At least for influenza vaccination, there is incontrovertible evidence that the elderly do respond much less effectively to vaccination than the young. As there are now several licensed prophylactic vaccines aimed at cancer prevention (including HPV, Hepatitis C, and other anti-virals), as well as non-anti-microbials in clinical trials (such as MUC-1 and PSCA), the immunocompetence of the recipients is likely to have a major impact on outcome.

In addition to immune manipulations and vaccination, there are also indirect manipulations of the immune response through the age-related inflammatory response such as by nutrition and lifestyle changes (Guo et al., 2009; Shammas, 2011), or specific micronutrient supplementation (Schmoranzer et al., 2009; Ames, 2010). These may be extremely important in a holistic approach to cancer treatment and for the general well-being of the elderly.

Conclusions

Based on present knowledge we can only suggest that the age-related immune alterations are likely to favor the development of tumors. There is little direct evidence that age-associated immune response changes are really important for controlling the development and progression of cancer. The best evidence comes from a few studies of immunotherapy in animal models. Most studies, both preclinical and clinical, have mostly been carried out in young animals, or patients not too advanced in age, but, as we discussed above, the effect of age on immunity is likely to be marked. Some immunotherapy models have specifically analyzed age as a variable affecting the outcome of treatment, in both active and adoptive settings. Intrinsic changes to DCs and extrinsic age-associated alterations in the host environment have been reported to exert a strong effect on triggering an anti-tumor response (Grolleau-Julius et al., 2009). Altered DC function, a potential problem also in younger individuals due to tumor-mediated suppression, might be amenable to correction by manipulating the costimulatory and/or cytokine environment. An immunotherapeutic model has been described using this approach which is effective in young but not in older mice. However, in the latter, certain adjuvants and exogenous IL-12 restore efficacy (Ruby at al., 2009). A similar approach but using a different immune modulator was shown to restore therapeutic activity in older animals (Tang et al., 2009). Other approaches have included demonstrations that immunotherapy protocols optimized for efficacy in young mice fail in older mice, but that immune modulators may improve results in the latter (Provinciali, 2009). In a spontaneous breast cancer model, differences in vaccine responses of young and old animals could be overcome, but only by using powerful adjuvants, improving costimulation, and at the same time reducing immune suppression (Lustgarten, 2009). However, this was achieved in concert with high levels of toxicity and treatment-associated death rates that would be unacceptable in humans. There is an important practical lesson here, given the older age of cancer patients: immunotherapy of cancer can be effective, but treating older individuals will be a challenge, as with most other forms of invasive geriatric treatments. It is therefore very important that separate cancer immunotherapy trials tailor-made specifically for the elderly are given high priority.

Disclosure

The authors declare no conflict of interest.

Acknowledgments

This work is partly supported by grants from the Canadian Institutes of Health Research (CIHR) (No. 106634 and No. 106701), the Université de Sherbrooke, and the Research Center on Aging.

Corresponding Authors

Tamas Fulop, M.D., Ph.D., Professor, Research center on Aging, University of Sherbrooke, 1036, rue Belvedere sud, Sherbrooke, QC, J1H 4C4, Canada

Graham Pawelec, M.A., Ph.D., Professor, Center for Medical Research, University of Tübingen, Waldhörnlestr. 22, D-72072 Tübingen, Germany.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(61):537-550, June 2011.]

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