Elsevier

Experimental Gerontology

Volume 107, 1 July 2018, Pages 27-36
Experimental Gerontology

Review
Considerations for successful cancer immunotherapy in aged hosts

https://doi.org/10.1016/j.exger.2017.10.002Get rights and content

Highlights

  • This article reviews major findings in age effects on immunity and how that affects cancer immunotherapy efficacy.

  • Differences and similarities between mouse models and human data are discussed.

  • This background is used to summarize key findings in efforts to use cancer immunotherapy successfully and optimally in aged patients.

  • Major reviews are addressed and original source data are discussed.

  • Areas for further investigations and testing are discussed.

Abstract

Improvements in understanding cancer immunopathogenesis have now led to unprecedented successes in immunotherapy to treat numerous cancers. Although aging is the most important risk factor for cancer, most pre-clinical cancer immunotherapy studies are undertaken in young hosts. This review covers age-related immune changes as they affect cancer immune surveillance, immunopathogenesis and immune therapy responses. Declining T cell function with age can impede efficacy of age-related cancer immunotherapies, but examples of successful approaches to breach this barrier have been reported. It is further recognized now that immune functions with age do not simply decline, but that they change in potentially detrimental ways. For example, detrimental immune cell populations can become predominant during aging (notably pro-inflammatory cells), the prevalence or function of suppressive cells can increase (notably myeloid derived suppressor cells), drugs can have age-specific effects on immune cells, and attributes of the aged microenvironment can impede or subvert immunity. Key advances in these and related areas will be reviewed as they pertain to cancer immunotherapy in the aged, and areas requiring additional study and some speculations on future research directions will be addressed. We prefer the term Age Related Immune Dysfunction (ARID) as most encompassing the totality of age-associated immune changes.

Introduction

The immune system can identify (and eliminate) cells expressing specific antigens with remarkable sensitivity. Tumors are theoretically highly antigenic tissues owing to their various mutations. Antigenicity, the expression of antigens, nonetheless does necessarily equal clinically useful immunogenicity (the capacity of antigens to provoke useful immunity). Thus, spontaneous rejection of clinically apparent tumors is a rare event. Work over the past 15 years shows how endogenous immunity fails to eradicate clinically through a multiplicity of factors including immunoediting (discussed below), umor-driven inflammation and immune dysfunction, and because tumor rejection antigens can be self antigens that are protected by autoimmune defense mechanisms (Pardoll, 2001, Pardoll, 2003). Recent work has advanced thinking towards anti-cancer immunotherapies with high potential for efficacy, which has now clearly been demonstrated clinically. As hosts age, these already-formidable barriers to treatment success become compounded, and additional barriers can emerge (Bouchlaka and Murphy, 2013, Bouchlaka et al., 2013, Hurez et al., 2012, Kaur et al., 2016).

Tumor immune surveillance is part of larger scheme of immunoediting (Schreiber et al., 2011), easily remember as involving three E's (Dunn et al., 2004). The first “E” is elimination of cancer cells as they initially emerge. The second “E” is equilibrium, in which malignant cells mutate to evolve immune elimination as the immune system evolves to attack new mutations. Selective pressures during equilibrium provoke tumor antigenic evolution that finally allows immune escape, the third “E”. In escape, the tumor can evade immune defenses and become clinically manifest, a process seen in mouse models (Koebel et al., 2007, Matsushita et al., 2012, DuPage et al., 2012) and in humans (Mittal et al., 2014, Strauss and Thomas, 2010, Stephens et al., 2000).

The original six fundamental cancer hallmarks (Hanahan and Weinberg, 2000) did not include lack of immune rejection, which was corrected with the revision to include additional fundamental hallmarks (Ward and Thompson, 2012). Generalized, chronic inflammation (Demaria et al., 2010, Grivennikov et al., 2010) is also considered a cancer hallmark (Colotta et al., 2009), as well as stem cell features (Teschendorff et al., 2010), genomic instability (Negrini et al., 2010), and abnormal vasculature (De Bock et al., 2010).

These cancer hallmarks (particularly immune rejection and chronic inflammation) affect age-specific immunotherapy development. Age effects on immunity extend far beyond simple declines in functions or reductions in cell numbers. We propose the term “Age Related Immune Dysfunction” (ARID) to encompass the full range of age-related alterations in immunity with advancing age. The following sections address major topics relating to age effects on cancer immunotherapy.

T cell immunity wanes with age owing to various processes affecting T cell numbers, diversity, phenotype and function (Hakim et al., 2004). As an example, CD45RA+ CD62L+ CD27+ CD28+ naive T cells are generated in thymus throughout life, but production decreases with age (Haynes et al., 2000), and thus T cell repertoire diversity declines with age as overall peripheral T cell numbers stay essentially the same (Surh et al., 2006). Hematopoietic stem cell generation of T cell precursors (Rossi et al., 2005) also declines. While naïve T cells decrease, there is a concomitant increase in memory T cells with age. Apparently terminally differentiated effector T cells (based on flow cytometry phenotype), including virus-reactive cells, with greatly reduced T cell receptor repertoire diversity and compromised potential to proliferate specifically increase (Fulop et al., 2013). T cell signaling, including through the T cell receptor also declines with age (Fulop et al., 2016).

Strategies to reduce age-related defects and improve T cell immunity have been tested. CD4+ T cell functions decline with age, but such loss can be partially overcome using cytokines including tumor necrosis factor (TNF)-α or interleukin (IL)-6 (Haynes et al., 2004). T cell priming (the activation of naïve, antigen-specific T cells) is defective in age, but can be improved with agonist αCD137 antibodies (Bansal-Pakala and Croft, 2002). Tumor-specific immunity can also be improved. For example, tumor control and anti-tumor T cell differentiation through OX40 signals decreases with age (Ruby and Weinberg, 2009a, Ruby and Weinberg, 2009b), but aged mice can be induced to mount protective antitumor immunity in a lymphoma model using an agonist αCD40 antibody (Lustgarten et al., 2004). We found that aged mice develop anti-tumor immunity comparable to that in young mice against B16 melanoma, a poorly immunogenic and highly aggressive tumor, by simultaneous reduction of age-increased suppressive myeloid and dysfunctional regulatory T cells (Hurez et al., 2012), which is discussed in detail below.

T cells (not necessarily cancer-specific) can improve host response to anti-cancer immunotherapy (Wang et al., 2016). It has been proposed that improving the function of aging T cells could improve cancer chemotherapy responses in the aged (Jackaman and Nelson, 2014), although this concept has not been tested to our knowledge.

Regulatory T cells (Tregs) mediate significant tumor immune dysfunction. Thus, inhibiting Treg function or reducing their numbers is under study as cancer immunotherapy (Curiel, 2007, Curiel, 2008, Curiel et al., 2004, Zou, 2006). Reports of Treg effects in age-related immune dysfunction are contradictory. Some studies showing show no changes or lessened Treg contributions (Kozlowska et al., 2007, Thomas et al., 2007), whereas other studies find increased age-related Treg function and/or prevalence in humans and mice (Zhang et al., 2008, Rosenkranz et al., 2007, Zhao et al., 2007, Kryczek et al., 2009). Treg prevalence in lymphoid organs but not thymus or blood has been reported in aged mice (Hurez et al., 2012, Sun et al., 2012, Lages et al., 2008).

Age effects on Treg functions depend on context and the specific function investigated. Some functions could be reduced (Tsaknaridis et al., 2003), such as suppressing delayed type hypersensitivity (Zhao et al., 2007), or inhibiting Th17 immunity (Sun et al., 2012). Aged Tregs mediate equal or greater suppression versus young mice in some reports (Hurez et al., 2012, Garg et al., 2014). Treg data in elderly humans is limited, but they could increase with age in blood (Fessler et al., 2013, Gregg et al., 2005). Tregs from young and elderly persons inhibited T cell proliferation similarly, but IL-10 (an anti-inflammatory cytokine) was lower in aged Tregs (Hwang et al., 2009).

Treg depletion can improve anti-tumor immunity and immunotherapy outcomes (Curiel, 2008, Zou, 2006), but reported Treg depletion effects in cancer immunotherapy in aged hosts are conflicting (Dominguez and Lustgarten, 2008, Sharma et al., 2006). One mouse study linked impaired tumor rejection to increased Tregs. In this study, αCD25 depleted Tregs and improved anti-cancer immunity (Sharma et al., 2006). We depleted Tregs in mice bearing B16 melanoma using denileukin diftitox (Hurez et al., 2012). Denileukin diftitox similarly depleted Tregs in young and aged mice, but it delayed tumor growth and augmented tumor-specific immunity only in young mice. Denileukin diftitox altered interferon-γ and IL-17 producing T cells distinctly in young versus aged mice. CD11b+ Gr-1hi myeloid derived suppressor cells (MDSC) were more numerous and suppressive in aged tumor-bearing aged mice, and depleting Tregs increased MDSC numbers even further.

We added anti-Gr-1 antibody to deplete MDSC along with Treg depletion, and restored anti-tumor immunity in the aged mice that slowed tumor growth comparable to Treg depletion in young hosts. Anti-Gr-1 antibody did not further augment anti-tumor immunity or tumor control in young mice as denileukin diftitox did not increase their MDSC. Dual Treg plus MDSC depletion increased interferon-γ-producing CD4+ and CD8+ T cells, and CD8+ tumor-specific T cells in aged mice, mirroring the effects on these T cell subsets seen in young mice treated with Treg depletion alone. To our knowledge this is the first cancer immunotherapy that treats aged, but not young hosts (Hurez et al., 2012). Fig. 1 outlines the differences in young versus aged mice accounting for differential treatment outcomes. Detailed data on age effects on human T cell subsets in responses to cancer immunotherapy are not yet reported to our knowledge.

Age effects of Tregs in human cancer immunotherapy are not yet specifically reported to our knowledge. In 209 melanoma patients receiving αCTLA-4 immunotherapy, high Tregs (and also eosinophils and lymphocytes) correlated with better clinical outcomes (Martens et al., 2016a), but age was not specifically assessed as a variable.

Lower T cell function and chronic, low-level age-related inflammation can increase suppressive myeloid cells. Thus, targeting aged innate cells could improve anti-tumor T cell functions in elderly cancer patients (Jackaman et al., 2014).

Dendritic cells (DCs) are antigen-presenting cells important in promoting T cell immunity (Palucka and Banchereau, 2012). The local tumor environment favors increasing numbers of dysfunctional DC that hinder anti-tumor immunity and immunotherapy outcomes (Zou et al., 2001, Curiel et al., 2003).

DC precursors in blood and Langerhans dendritic cells in skin, conventional DC in other organs and DC generation from bone marrow can all decrease with advancing age, which could contribute to reduced protective immunity with age. By contrast, other DC subsets, notably those with potential autoimmune reactivity can increase in certain animal models of autoimmunity, which could help explain the age-related propensity for autoimmunity, described in detail in (Ishikawa et al., 2001, Ishikawa et al., 2002).

Distinct DC functions with age can be decreased or unchanged depending on the function, such as reduced alloreactivity in a mixed lymphocyte reaction, reduced T cell activation molecules (e.g., MHC class II, ICAM-1), reduced migration and antigen capture capacity, and reduced cytokine or chemokine production, reviewed extensively in (Agrawal et al., 2008). Some of these effects are DC-intrinsic whereas others (such as reduced migration) could be attributable to defective host factors. If declining or altered DC functions reduce T cell function or promote inflammation, that could increase age-related cancer risk. Augmenting the capacity of DC to present antigens, a function that can decline with age, induces potent tumor-specific cytotoxic T cell activities. CD40L or agonist anti-CD40 antibodies augment DC activation in human and animal studies (Khong et al., 2012). A vaccine consisting of CD40L physically linked to specific cancer antigens showed promise in older cancer patients (Tang et al., 2009).

In aged humans, reduced Langerhans DC have also been reported (Ghersetich and Lotti, 1994). The two principal circulating human DC subsets (myeloid and plasmacytoid) also appear to decline in numbers and function with age as does DC generation from bone marrow, all effects similar to those seen in aged mice, reviewed in (Agrawal et al., 2008). Interestingly, although in situ DC from the aged humans have apparent functional defects, when DC are generated from aged precursors (such as monocyte-derived DC), their numbers and functions appear similar to those from young precursors. Thus, DC-based cancer immunotherapies based on generation from precursor cells could be a viable strategy in aged cancer patients. The effects of age on tumor microenvironment-driven DC dysfunction in humans are not reported to our knowledge, but would be useful to know.

Myelopoiesis increases in age (Geiger and Rudolph, 2009), leading to increased myeloid cell numbers. Macrophages are important elements of tumor stroma and contribute to tumor-associated immune dysfunction (Mantovani et al., 2008). Tumor macrophages can be pro-inflammatory M1 or anti-inflammatory M2 macrophages, and these phenotypes can interconvert. M1 macrophages produce pro-inflammatory cytokines including TNF-α and IL-12 that augment anti-tumor immunity. M2 macrophages are generally anti-inflammatory and produce cytokines such as IL-10 and TGF-β that promote tumorigenesis or angiogenesis (Mantovani et al., 2008).

Macrophages increase in lymphoid organs of aged mice (Jackaman et al., 2013). M1 macrophage functions could increase because of increased age-related reactive oxygen species, but others report reduced M1 macrophage function with age (Mahbub et al., 2012), perhaps from IL-10 producing M2 macrophages that increase with age (Mantovani et al., 2008). Tumor-associated macrophages from aged mice produce high levels of transforming growth factor (TGF)-β that can be immunosuppressive, consistent with an M2-type phenotype, whereas young macrophages do not (Jackaman et al., 2013). Detrimental M2 macrophages can be converted to beneficial M1 using IL-12 or CpG plus an αIL-10 receptor (Watkins et al., 2007). Thus targeting tumor-associated age-related M2 macrophages could be useful to treat cancers in aged hosts.

The distribution and some functions of macrophages in aged hosts differ from the young. For example, M1 macrophages with a pro-inflammatory phenotype are increased in liver and fat tissues of normal aged hosts versus young hosts whereas anti-inflammatory/immune suppressive M2 macrophages are more prevalent in normal aged versus young hosts in peripheral lymphoid tissues, reviewed in (Jackaman et al., 2017). However, effects in cancer, and whether macrophages from aging hosts are especially prone to promote tumor growth in not fully settled and likely will depend on the specific tumor and/or anatomic site.

Myeloid derived suppressor cells (MDSC) are immunosuppressive, immature myeloid cells that are elevated in inflammatory diseases including cancers (Ostrand-Rosenberg and Sinha, 2009, Li et al., 2009, Youn et al., 2008, Marigo et al., 2008) and they suppress anti-tumor immunity (Huang et al., 2006). MDSCs produce inhibitory molecules (e.g., arginase, IL-10) that inhibit T cell functions, and can promote generation of detrimental M2 macrophages or Tregs (Marvel and Gabrilovich, 2015). MDSCs increase in blood during human aging (Verschoor et al., 2013) and increase in lymphoid organs in mice (Hurez et al., 2012, Jackaman et al., 2013). MDSC are immunopathologic in age including in aged hosts with cancer (Grizzle et al., 2007, Enioutina et al., 2011). Treg depletion using denileukin diftitox increased MDSC numbers in aged mice bearing B16 melanomas, suggesting MDSC control by Tregs (Hurez et al., 2012). In CT26 colon cancer, an extract of Lentinula edodes mycelia reduced MDSC numbers when combined with a cancer vaccine in aged mice. The proposed mechanism was suppression of IL-6 and TNF-α known to promote MDSC (Ishikawa et al., 2016). This mycelium extract also improved priming of tumor-specific cytotoxic T cells by the vaccine. Thus, MDSC are an attractive target to develop potentially effective approaches to mitigate cancer-associated immune dysfunction in the aged host.

Age effects of MDSC in human cancer immunotherapy are not yet specifically reported to our knowledge. In 209 patients receiving αCTLA-4 as melanoma immunotherapy, low baseline blood MDSC (and also lactic acid dehydrogenase and monocytes) correlated with better clinical outcomes (Martens et al., 2016a), but age was not independently assessed.

Aging B cells can be dysfunctional to normal immune homeostasis by producing tumor necrosis factor-α that is detrimental (Ratliff et al., 2015). We showed that in aged mice aging-associated PD-L2-expressing B cells enhance anti-tumor immunity to ovarian cancer via Th1 and Th17 induction (Tomihara et al., 2012). Little else regarding B cells in anti-tumor immunity or response to immunotherapy has been reported to our knowledge.

As many immune cells come from hematopoietic stem cells, which themselves are subject to aging effects, understanding aging of hematopoietic stem cells could provide insights into improving an aging immune system. Progress on this front has been made (Florian et al., 2013).

With age, novel immune cell subsets appear, including those with potential to deviate anti-tumor immunity or immunotherapy responses. We described PD-L2-expressing B cells that increase with age and enhance anti-tumor immunity to ovarian cancer via Th1 and Th17 induction. These cells were not seen in young mice (Tomihara et al., 2012). CD25lo Tregs appear with age in normal mice (Nishioka et al., 2006), in contrast to conventional CD25hi Tregs in young hosts. These are slightly hypofunctional versus CD25hi Tregs but we did not define clear immunopathologic significance in cancer immunotherapy of aged mice with B16 melanoma although denileukin diftitox reduced their numbers (Hurez et al., 2012).

Section snippets

Immune checkpoint inhibitors

Immune checkpoint receptor blockade is a highly successful immunotherapy strategy for various cancers (Pardoll and Drake, 2012, Pardoll, 2012). Six distinct checkpoint inhibitor antibody treatments were FDA approved as cancer immunotherapy for a wide variety of cancers at the time of this writing, with more approvals expected soon. Nonetheless, effects in elderly patients are little reported.

Immune checkpoint molecules control the magnitude of immune responses either positively (activating) or

Tumor microenvironment

The tumor microenvironment includes the tumor itself, infiltrating immune cells, stromal cells and matrix components. The aged tumor microenvironment has aspects that suggest it could be more immunosuppressive versus in young hosts (Hurez et al., 2017). Such aspects include increased M2 macrophages and MDSC that could be attributable to chronic, low grade age-related inflammation. Other factors include tumor cells that can attract detrimental MDSC, neutrophils or Tregs that blunt anti-tumor

Immunotherapy toxicity mitigation

In aged mice, cancer immunotherapy can be lethal or produce local toxicities or toxicities in distinct organs, in part due to pro-inflammatory cytokines that are generated locally in affected tissues and systemically. Macrophages appear to be prime drivers of pro-inflammatory effects over T cells or natural killer cells. Depletion of myeloid cells concomitantly with therapy can mitigate toxicities and yet not compromise treatment efficacy significantly. Aged macrophages from mice and from

Microbiome effects

Gut microbes affects systemic immunity and the gut microbial composition is altered by age (Yatsunenko et al., 2012, Pitt et al., 2016, Zitvogel et al., 2016). In two separate papers gut microbes were shown to affect anti-cancer immunotherapy in human subjects being treated with αPD-L1 (Sivan et al., 2015) or αCTLA-4 (Vetizou et al., 2015). At present, there is much justified interest in defining microbial effects on anti-cancer immunity. Age effects in this regard are not yet reported on

Conclusions

Cancer immunotherapy has a strong scientific rationale. Recent advances in understanding details of cancer driven immune dysfunction have helped develop highly successful, although still imperfect, anti-cancer immunotherapies. Much of our understanding of anti-tumor immunity and responses to cancer immunotherapy derives from studies of relatively young hosts. A growing, but still relatively small body of data is beginning to define age effects on cancer immunity and responses to

Challenges in developing effective age-appropriate cancer immunotherapy

Understanding age effects on tumor-specific immunopathology and related age-specific effects better will help in development of more effective treatments. Individual agents are unlikely to be effective cancer treatments, and thus means to combine agents and approaches optimally needs further definition, including age-specific agents, doses and schedules. Biomarkers that differentiate aged patients with potential to generate tumor-specific immunity to selected agents from those patients

Acknowledgements

VH, RSS and TJC wrote the manuscript. VH and AP performed some experiments described.

Conflict of interest

The authors declare no financial conflicts.

Financial support

Tyler Curiel (CA170491, CA54174, CDMRP, The Holly Beach Public Library, The Owens Foundation, The Barker Foundation and the Skinner Endowment).

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