Western and third world countries alike are experiencing population ageing with people living longer.The World Health Organization website states that 'between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22% reaching 2.1 billion', and that 'the number of persons aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million'.However, the elderly (i.e., those aged over 65 years) are 11 times more likely to develop cancer than younger people; this is illustrated by GLOBOCAN 2020 data showing that greater than 50% of people who had cancer were 65 or older in 2018.This age-related cancer emergence may in part be due to increasing dysregulation of the immune system or "immunosenescence".Macrophages are pivotal immune cells in maintaining homeostasis and in regulating inflammatory responses during immunological insults, such as cancer, where they can perform anti-tumourigenic functions.Yet, tumour-associated macrophages are well known for their ability to promote tumour growth, with numbers often correlating to cancer progression and poorer outcomes.Macrophages contribute to this by secreting growth and angiogenic factors, and they closely interact with endothelial cells and cancer cells to help shape the tumour microenvironment.During ageing, macrophage response to environmental stimuli becomes dysregulated including impaired anti-tumour functions.Furthermore, increased number of macrophages and precursor cells are observed in lymphoid organs that can supply to tumours with ageing.Such age-related changes, including those to endothelial cells, may promote cancer development and lead to poorer cancer outcomes in elderly people.In this review, we discuss recent findings concerning how macrophages are modulated during healthy ageing and in cancer, with a focus on macrophage and endothelial cell interactions.

Anti-disialoganglioside (GD2) antibody therapy has provided clinical benefit to patients with neuroblastoma however efficacy is likely impaired by the immunosuppressive tumor microenvironment. We have previously defined a link between intratumoral copper levels and immune evasion. Here, we report that adjuvant copper chelation potentiates anti-GD2 antibody therapy to confer durable tumor control in immunocompetent models of neuroblastoma. Mechanistic studies reveal copper chelation creates an immune-primed tumor microenvironment through enhanced infiltration and activity of Fc-receptor-bearing cells, specifically neutrophils which are emerging as key effectors of antibody therapy. Moreover, we report copper sequestration by neuroblastoma attenuates neutrophil function which can be successfully reversed using copper chelation to increase pro-inflammatory effector functions. Importantly, we repurpose the clinically approved copper chelating agent Cuprior as a non-toxic, efficacious immunomodulatory strategy. Collectively, our findings provide evidence for the clinical testing of Cuprior as an adjuvant to enhance the activity of anti-GD2 antibody therapy and improve outcomes for patients with neuroblastoma.

It is becoming increasingly clear that the tumour microenvironment (TME) adopts a changing and increasingly complex landscape as tumours evolve. Central to the TME, and alongside malignant cells, are tissue resident and recruited macrophages, other immune cells, and endothelial cells, with the latter critical for angiogenesis and tumour development. Tumour vessels provide oxygen and nutrients and are portals for immune cells. Tumour cells, immune cells and endothelial cells engage in multi-directional crosstalk that untimately influence tumour progression and treatment responses. Adding to complexity, the TME often consists of oxygenated, and oxygen deprived or hypoxic regions, with the latter significantly contributing to disease progression and treatment resistance. However, the function of immune cells and endothelial cells change with ageing, and this underexplored area likely influences the aged TME and disease outcomes in the elderly. Solid cancers such as mesothelioma with known carcinogen exposure (asbestos) take decades to reach a diagnosable size, often emerging in people aged 60 years or more. Here, we discuss the influence of ageing on the function of tumour-associated immune cells, focussing on macrophages, and their possible interactions with endothelial cells, and how this might impact the evolving mesothelioma TME in elderly people.

It is now well accepted that the immune system can protect from cancer, with checkpoint immunotherapy becoming standard of care for some cancers. However, immune function declines with age and most cancers emerge in the elderly. For example, mesothelioma emerges 30–40 years after exposure to asbestos, with most patients being greater than 60 years old. Studies in young (6–8 week old) mice that are equivalent to 14–16 year old humans have shown that several chemotherapeutic agents require a functional T cell response to elicit an effective anti-cancer outcome. But T cells become increasingly dysfunctional with ageing. We have shown that innate immune cells including dendritic cells and macrophages demonstrate loss of function with ageing. We also found that tumours grew faster in elderly mice (24–27 month old, equivalent to 70–80 human years); this was associated with cancer cachexia that was not seen in young mice. Chemotherapy induced even more weight loss and liver damage in elderly but not young mice, and was not as effective in elderly mice. Moreover, we also found that young mice generated a significant tumour specific CD8+ T cell response, whilst elderly mice generated only a weak tumour specific T cell response during tumour progression. Nonetheless, chemotherapy in elderly mice still required T cells to induce tumour regression. Finally, using mice and pet dogs with naturally occurring cancer, we identified an immunotherapy that helps restore immune function in the elderly.

The importance of the immune microenvironment in triple negative and HER2amplified breast cancer (BC) is well-established; less is known about the immune environment in luminal breast cancers. We aimed to assess for the impact of immune biomarkers on BC outcome in a group of luminal B patients with archived tissue and annotated clinical information. Patients with early breast cancer (EBC) treated in a single institution over a 14-year period, with prospectively collected data were included. Luminal B EBC patients were identified and defined into three cohorts: A: grade 2 or 3, ER & PR positive, HER2-negative; B: Any grade, ER positive, PR and HER2-negative (Ki67 >= 14% in cohorts A & B); and C: Any grade, ER or PR positive, HER2-positive. Within each cohort, patients with a relapsed BC event (R) were compared on a 1:1 basis with a control patient (C) who remained disease free, balanced for key characteristics in an effort to balance the contribution of each clinical group to outcome. Archival breast, involved and uninvolved axillary nodes were assessed by immunohistochemistry for biomarkers identifying effector and suppressor immune cells, and compared between R and C. In total, 120 patients were included (80, 22, and 18 patients in cohorts A, B, and C, respectively). R were 1.5 years older (p = 0.016), with all other characteristics being balanced. Overall, there were no statistically significant differences in immune biomarkers in breast or nodal tissue of R and C. However, there was a trend toward higher levels of TILs in breast tumors of C, while GAL-9 was consistently expressed on lymphocytes and tumor cells in all breast and nodes of C and was absent from all tissues of R. These trends in checkpoint molecule expression deserve further research.

Increased cancer incidence occurs with the emergence of immunosenescence, highlighting the indispensability of the immune system in preventing cancer and its dysregulation with aging. Tumor-associated macrophages (TAMs) are often present in high numbers and are associated with poor clinical outcomes in solid cancers, including mesothelioma. Monocytes and macrophages from the bone marrow and spleen can respond to tumor-derived factors, such as CSF-1, and initiation of the CSF-1R signaling cascade results in their proliferation, differentiation, and migration to the tumor. Age-related changes occur in monocytes and macrophages in terms of numbers and function, which in turn can impact tumor initiation and progression. Whether this is due to changes in CSF-1R expression with aging is currently unknown and was investigated in this study. We examined monocytes and macrophages in the bone marrow and spleen during healthy aging in young (3–4 months) and elderly (20–24 months) female C57BL/6J mice. Additionally, changes to these tissues and in TAMs were examined during AE17 mesothelioma tumor growth. Healthy aging resulted in an expansion of Ly6Chigh monocytes and macrophages in the bone marrow and spleen. CSF-1R expression levels were reduced in elderly splenic macrophages only, suggesting differences in CSF-1R signaling between both cell type and tissue site. In tumor-bearing mice, Ly6Chigh monocytes increased with tumor growth in the spleen in the elderly and increased intracellular CSF-1R expression occurred in bone marrow Ly6Chigh monocytes in elderly mice bearing large tumors. Age-related changes to bone marrow and splenic Ly6Chigh monocytes were reflected in the tumor, where we observed increased Ly6Chigh TAMs earlier and expansion of Ly6Clow TAMs later during AE17 tumor growth in the elderly compared to young mice. F4/80high TAMs increased with tumor growth in both young and elderly mice and were the largest subset of TAMs in the tumor. Together, this suggests there may be a faster transition of Ly6Chigh towards F4/80high TAMs with aging. Amongst TAM subsets, expression of CSF-1R was lowest in F4/80high TAMs, however Ly6Clow TAMs had higher intracellular CSF-1R expression. This suggests downstream CSF-1R signaling may vary between macrophage subsets, which can have implications towards CSF-1R blockade therapies targeting macrophages in cancer.

AbstractHuman and canine sarcomas are difficult to treat soft tissue malignancies with an urgent need for new improved therapeutic options. Local recurrence rates for humans are between 10%–30%, and 30%–40% develop metastases. Outcomes for dogs with sarcoma vary with grade but can be similar. Pet dogs share the human environment and represent human cancer with genetic variation in hosts and tumours. We asked if our murine studies using genetically identical mice and cloned tumour cells were translatable to larger, genetically diverse domestic dogs with naturally occurring tumours, to (i) develop a canine cancer therapeutic, and (ii) to use as a translational pathway to humans. Our murine studies showed that intra‐tumoral delivery of interleukin‐2 (IL‐2) plus an agonist anti‐CD40 antibody (Ab) induces long‐term curative responses ranging from 30% to 100%, depending on tumour type. We developed an agonist anti‐canine‐CD40 Ab and conducted a phase I dose finding/toxicology 3 + 3 clinical trial in dogs (n = 27) with soft tissue sarcomas on account of suitability for intratumoral injection and straightforward monitoring. Dogs were treated with IL‐2 plus anti‐CD40 antibody for 2 weeks. Three dose levels induced tumour regression with minimal side effects, measured by monitoring, haematological and biochemical assays. Importantly, our mouse and canine studies provide encouraging fundamental proof‐of‐concept data upon which we can develop veterinary and human immunotherapeutic strategies.

We assessed the murine Stimulator of Interferon Genes (STING) agonist, DMXAA, for anti-mesothelioma potential using the AE17-sOVA model that expresses ovalbumin (OVA) as a neo tumor antigen. Dose response experiments alongside testing different routes of administration identified a safe effective treatment regimen that induced 100% cures in mice with small or large tumors. Three doses of 25mg/kg DMXAA given intra-tumorally every 9 days induced tumor regression and long-term survival (>5 months). Re-challenge experiments showed that tumor-free mice developed protective memory. MTT and propidium-iodide assays showed that DMXAA exerted direct cytotoxic effects at doses >1mg/ml on the murine AE17 and AB1 mesothelioma cell lines. In-vivo studies using a CFSE-based in-vivo proliferation assay showed that DMXAA improved tumor-antigen presentation in tumor-draining lymph nodes, evidenced by OVA-specific OT-1 T cells undergoing more divisions. An in-vivo cytotoxic T lymphocyte (CTL) assay showed that DMXAA blunted the lytic quality of CTLs recognizing the dominant (SIINFEKL) and a subdominant (KVVRFDKL) OVA epitopes. DMXAA reduced tumor vessel size in-vivo and although the proportion of T cells infiltrating tumors reduced, the proportion of tumor-specific T cells increased. These data show careful dosing and treatment protocols reduce mesothelioma cell viability and modulate tumor vessels such that tumor-antigen specific CTLs access the tumor site. However, attempts to enhance DMXAA-induced anti-tumor responses by combination with an agonist anti-CD40 antibody or IL-2 reduced efficacy. These proof-of-concept data suggest that mesothelioma patients could benefit from treatment with a STING agonist, but combination with immunotherapy should be cautiously undertaken.

Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

The immune system, and in particular, cytotoxic CD8+ T cells (CTLs), plays a vital part in the prevention and elimination of tumors. In many patients, however, CTL-mediated tumor killing ultimately fails in the clearance of cancer cells resulting in disease progression, in large part due to the progression of effector CTL into exhausted CTL. While there have been major breakthroughs in the development of CTL-mediated "reinvigoration"-driven immunotherapies such as checkpoint blockade therapy, there remains a need to better understand the drivers behind the development of T cell exhaustion. Our study highlights the unique differences in T cell exhaustion development in tumor-specific CTL which arises over time in a mouse model of mesothelioma. Importantly, we also show that peripheral tumor-specific T cells have a unique expression profile compared to exhausted tumor-infiltrating CTL at a late-stage of tumor progression in mice. Together, these data suggest that greater emphasis should be placed on understanding contributions of individual microenvironments in the development of T cell exhaustion.

Increasing life expectancy is associated with increased cancer incidence, yet the effect of cancer and anti-cancer treatment on elderly patients and their immune systems is not well understood. Declining T cell function with aging in response to infection and vaccination is well documented, however little is known about aged T cell responses to tumor antigens during cancer progression or how these responses are modulated by standard chemotherapy. We examined T cell responses to cancer in aged mice using AE17sOVA mesothelioma in which ovalbumin (OVA) becomes a spy' tumor antigen containing one dominant (SIINFEKL) and two subdominant (KVVRFDKL and NAIVFKGL) epitopes. Faster progressing tumors in elderly (22-24months, cf. 60-70 human years) relative to young (2-3months, human 15-18years) mice were associated with increased pro-inflammatory cytokines and worsened cancer cachexia. Pentamer staining and an in-vivo cytotoxic T lymphocyte (CTL) assay showed that whilst elderly mice generated a greater number of CD8(+) T cells recognizing all epitopes, they exhibited a profound loss of function in their ability to lyse targets expressing the dominant, but not subdominant, epitopes compared to young mice. Chemotherapy was less effective and more toxic in elderly mice however, similar to young mice, chemotherapy expanded CTLs recognizing at least one subdominant epitope in tumors and draining lymph nodes, yet treatment efficacy still required CD8(+) T cells. Given the significant dysfunction associated with elderly CTLs recognizing dominant epitopes, our data suggest that responses to subdominant tumor epitopes may become important when elderly hosts with cancer are treated with chemotherapy.

The synthesis, structural and photophysical characterisation of four tricarbonyl rhenium(i) complexes bound to 1,10-phenanthroline and a tetrazolato ancillary ligand are reported. The complexes are differentiated by the nature (hydroxy or methoxy) and position (meta or para) of the substituent attached to the phenyl ring in conjugation to the tetrazole ring. The complexes exhibit phosphorescence emission from triplet charge transfer excited states, with the maxima around 600 nm, excited state lifetime decays in the 200-300 ns range, and quantum yield values of 4-6% in degassed acetonitrile solutions. The nature and position of the substituent does not significantly affect the photophysical properties, which remain unchanged even after deprotonation of the hydroxide group on the phenol ring. The interpretation of the photophysical data was further validated by resonance Raman spectroscopy and time-dependent density functional theory calculations. All the complexes are internalised within cells, albeit to variable degrees. As highlighted by a combination of flow cytometry and confocal microscopy, the species display diffuse cytoplasmic localisation except for the complex with the hydroxy functional group at the para position, which reveals lower accumulation in cells and more pronounced punctate staining. Overall, the complexes displayed low levels of cytotoxicity.

Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. The immune system plays a critical role in the effectiveness of many anticancer therapies in young hosts via tumor-specific T cells. However, immunosuppressive macrophages can constitute up to 50% of the tumor burden and impair anti-tumor T cell activity. Altered macrophage phenotype and function during aging may further impact anti-tumor T cell responses. Yet, the impact of macrophages on anti-tumor T cell responses and immunotherapy in the elderly is unknown. Therefore, we examined macrophages and their interaction with T cells in young (3 months) and elderly (20-24 months) AE17 mesothelioma-bearing female C57BL/6J mice during tumor growth. Mesothelioma tumors grew faster in elderly compared with young mice, and this corresponded with an increase in tumor-associated macrophages. During healthy aging, macrophages increase in bone marrow and spleens suggesting that these sites have an increased potential to supply cancer-promoting macrophages. Interestingly, in tumor-bearing mice, bone marrow macrophages increased proliferation whilst splenic macrophages had reduced proliferation in elderly compared with young mice, and macrophage depletion using the F4/80 antibody slowed tumor growth in young and elderly mice. We also examined responses to treatment with intra-tumoral IL-2/anti-CD40 antibody immunotherapy and found it was less effective in elderly (38% tumor regression) compared to young mice (90% regression). Tumor-bearing elderly mice decreased in vivo anti-tumor cytotoxic T cell activity in tumor draining lymph nodes and spleens. Depletion of macrophages using F4/80 antibody in elderly, but not young mice, improved IL-2/anti-CD40 immunotherapy up to 78% tumor regression. Macrophage depletion also increased in vivo anti-tumor T cell activity in elderly, but not young mice. All the tumor-bearing elderly (but not young) mice had decreased body weight (i.e., exhibited cachexia), which was greatly exacerbated by immunotherapy; whereas macrophage depletion prevented this immunotherapy-induced cachexia. These studies strongly indicate that age-related changes in macrophages play a key role in driving cancer cachexia in the elderly, particularly during immunotherapy, and sabotage elderly anti-tumor immune responses.

The average age of the human population is rising, leading to an increasing burden of age-related diseases, including increased susceptibility to infection. However, immune function can decrease with age which could impact on processes that require a functional immune system. Aging is also characterized by chronic low-grade inflammation which could further impact immune cell function. While changes to neutrophils in blood during aging have been described, little is known in aging lymphoid organs. This study used female C57BL/6J mice comparing bone marrow (BM), spleen and lymph nodes from young mice aged 2–3 months (equivalent to 18 human years) with healthy elderly mice aged 22–24 months (equivalent to 60–70 human years). Neutrophil proportions increased in BM and secondary lymphoid organs of elderly mice relative to their younger counterparts and presented an atypical phenotype. Interestingly, neutrophils from elderly spleen and lymph nodes were long lived (with decreased apoptosis via Annexin V staining and increased proportion of BrdU neg mature cells) with splenic neutrophils also demonstrating a hypersegmented morphology. Furthermore, splenic neutrophils of elderly mice expressed a mixed phenotype with increased expression of activation markers, CD11b and ICAM-1, increased proinflammatory TNFα, yet increased anti-inflammatory transforming growth factor-beta. Elderly splenic architecture was compromised, as the marginal zone (required for clearing infections) was contracted. Moreover, neutrophils from elderly but not young mice accumulated in lymph node and splenic T- and B-cell zones. Overall, the expansion of functionally compromised neutrophils could contribute to increased susceptibility to infection observed in the elderly.

Aging is associated with an increased incidence of cancer. One contributing factor could be modulation of immune cells responsible for anti-tumor responses, such as dendritic cells (DCs) and T cells. These immunological changes may also impact the efficacy of cancer immunotherapies in the elderly. The effects of healthy aging on DCs and T cells, and their impact on anti-mesothelioma immune responses, had not been reported. This study examined DCs and T cells in young (2-5 months; equivalent to 16-26 human years) and elderly (20-24 months; equivalent to 60-70 human years) healthy and mesothelioma-bearing C57BL/6J mice. During healthy aging, elderly lymph nodes adopted a regulatory profile, characterized by: (i) increased plasmacytoid DCs, (ii) increased expression of the adenosine-producing enzyme CD73 on CD11c+ cells, and (iii) increased expression of multiple regulatory markers (including CD73, the adenosine A2B receptor, CTLA-4, PD-1, ICOS, LAG-3, and IL-10) on CD8+ and CD4+ T cells, compared to lymph nodes from young mice. Although mesotheliomas grew faster in elderly mice, the increased regulatory status observed in healthy elderly lymph node DCs and T cells was not further exacerbated. However, elderly tumor-bearing mice demonstrated reduced MHC-I, MHC-II and CD80 on CD11c+ cells, and decreased IFN-γ by CD8+ and CD4+ T cells within tumors, compared to young counterparts, implying loss of function. An agonist CD40 antibody based immunotherapy was less efficient at promoting tumor regression in elderly mice, which may be due to: (i) failure of elderly CD8+ T cells to up-regulate perforin, and (ii) increased expression of multiple regulatory markers on CD11c+ cells and T cells in elderly tumor-draining lymph nodes (including CD73, PD-1, ICOS, LAG-3, and TGF-β). Our findings suggest that checkpoint blockade may improve responses to immunotherapy in elderly hosts with mesothelioma, and warrants further investigation.

The average age of the human population is rising, leading to an increasing burden of age‐related diseases, including increased susceptibility to infection. However, immune function can decrease with age which could impact on processes that require a functional immune system. Aging is also characterized by chronic low‐grade inflammation which could further impact immune cell function. While changes to neutrophils in blood during aging have been described, little is known in aging lymphoid organs. This study used female C57BL/6J mice comparing bone marrow (BM), spleen and lymph nodes from young mice aged 2–3 months (equivalent to 18 human years) with healthy elderly mice aged 22–24 months (equivalent to 60–70 human years). Neutrophil proportions increased in BM and secondary lymphoid organs of elderly mice relative to their younger counterparts and presented an atypical phenotype. Interestingly, neutrophils from elderly spleen and lymph nodes were long lived (with decreased apoptosis via Annexin V staining and increased proportion of BrdU neg mature cells) with splenic neutrophils also demonstrating a hypersegmented morphology. Furthermore, splenic neutrophils of elderly mice expressed a mixed phenotype with increased expression of activation markers, CD11b and ICAM‐1, increased proinflammatory TNFα, yet increased anti‐inflammatory transforming growth factor‐beta. Elderly splenic architecture was compromised, as the marginal zone (required for clearing infections) was contracted. Moreover, neutrophils from elderly but not young mice accumulated in lymph node and splenic T‐ and B‐cell zones. Overall, the expansion of functionally compromised neutrophils could contribute to increased susceptibility to infection observed in the elderly.

There is evidence that dendritic cells (DCs) undergo age-related changes that modulate their function with their key role being priming antigen-specific effector T cells. This occurs once DCs develop into antigen-presenting cells in response to stimuli/danger signals. However, the effects of aging on DC responses to bacterial lipopolysaccharide (LPS), the pro-inflammatory cytokine interferon (IFN)-γ and CD40 ligand (CD40L) have not yet been systematically evaluated. We examined responses of blood myeloid (m)DC1s, mDC2s, plasmacytoid (p)DCs, and monocyte-derived DCs (MoDCs) from young (21-40 years) and elderly (60-84 years) healthy human volunteers to LPS/IFN-γ or CD40L stimulation. All elderly DC subsets demonstrated comparable up-regulation of co-stimulatory molecules (CD40, CD80 and/or CD86), intracellular pro-inflammatory cytokine levels (IFN-γ, tumour necrosis factor (TNF)-α, IL-6 and/or IL-12), and/or secreted cytokine levels (IFN-α, IFN-γ, TNF-α, and IL-12) to their younger counterparts. Furthermore, elderly-derived LPS/IFN-γ or CD40L-activated MoDCs induced similar or increased levels of CD8+ and CD4+ T cell proliferation, and similar T cell functional phenotypes, to their younger counterparts. However, elderly LPS/IFN-γ-activated MoDCs were unreliable in their ability to up-regulate chemokine (IL-8 and monocyte chemoattractant protein (MCP)-1) and IL-6 secretion, implying an inability to dependably induce an inflammatory response. A key age-related difference was that, unlike young-derived MoDCs that completely lost their ability to process antigen, elderly-derived MoDCs maintained their antigen processing ability after LPS/IFN-γ maturation, measured using the DQ-ovalbumin assay; this response implies incomplete maturation that may enable elderly DCs to continuously present antigen. These differences may impact on the efficacy of anti-pathogen and anti-tumour immune responses in the elderly.

Factors are reviewed that contribute to the contemporary view of a disproportionate prevalence and incidence of SLE in females. Recent studies on the epidemiology of SLE report that global incidences and prevalences of SLE for Caucasian and Black populations are of the order of 5.5 and 13.1 per year and 81 and 212 per 100,000 persons respectively. Both parameters displayed age dependent variation over a 90-year lifespan. The female to male (F:M) incidence of SLE varied with age, being approximately 1 during the first decade of life, followed by a sharp increase to 9 during the 4th decade, thence declining in subsequent decades before an increase during the 7th or 8th decade. A cognate review of SLE diagnosis in neonates revealed a F:M ratio of ≈1.2, consistent with the epidemiology review and the sporadic nature of SLE. Notional estimates of disease duration showed a steady increase from a base level for both males and females. The linear trend line for males was always lower than the trend line for females, supporting clinical experience that SLE is a more severe disease in males. Over a 14-year interval ending in 2012, the notional duration of SLE increased from 10-15years to 20-25years, probably reflecting advances in diagnosis and clinical practice. A metastudy of SLE concordance in twins revealed a 75% discordance in monozygotic twins compared to a 95% discordance in dizygotic twins confirming the importance of environmental factors in susceptibility to SLE. The elevated discordance in dizygotic SLE twins (and between siblings) suggests a role for the intrinsic genomic sexual dimorphism due to divergence of Y chromosome regulatory loci from their X chromosome homologues due to lack of recombination of mammalian sex chromosomes over evolutionary time. Estimates were made of the incidences of SLE in males and females based on population data for nine autosomal deficiency loci of major effect, plus expected male prevalence associated with Klinefelter's syndrome and female prevalence associated with Triple X syndrome. These genetic abnormalities accounted for ≈4% of female and ≈23% of male Caucasoid prevalence and for SLE resulting in a F:M ratio of ≈0.17. It may be deduced therefore that the impressive preponderance of SLE in females arises from a combination of environmental triggers and susceptibility loci of relatively small effect acting between the interval from the mini-puberty of childhood to the peak of reproductive adulthood. It is in this cohort of females, and especially in the Black population, that combinations of loci of minor effect acting together with environmental factors initiate defective apoptosis resulting in consequential autoimmune disease especially SLE. We postulate that because apoptosis is itself a very complex process, and defective apoptosis is an important contributor to SLE, there will be many combinations of susceptibility loci and environmental stimuli that can result in SLE (and other autoimmune disease(s)), of varying severity.

Impaired immune function has been implicated in the declining health and higher incidence of cancer in the elderly. However, age-related changes to immunity are not completely understood. Neutrophils and macrophages represent the first line of defence yet their ability to phagocytose pathogens decrease with aging. Cytotoxic T lymphocytes are critical in eliminating tumors, but T cell function is also compromised with aging. T cell responses can be regulated by macrophages and may depend on the functional phenotype macrophages adopt in response to microenvironmental signals. This can range from pro-inflammatory, anti-tumorigenic M1 to anti-inflammatory, pro-tumorigenic M2 macrophages. Macrophages in healthy elderly adipose and hepatic tissue exhibit a more pro-inflammatory M1 phenotype compared to young hosts whilst immunosuppressive M2 macrophages increase in elderly lymphoid tissues, lung and muscle. These M2-like macrophages demonstrate altered responses to stimuli. Recent studies suggest that neutrophils also regulate T cell function and, like macrophages, neutrophil function is modulated with aging. It is possible that age-modified tissue-specific macrophages and neutrophils contribute to chronic low-grade inflammation that is associated with dysregulated macrophage-mediated immunosuppression, which together are responsible for development of multiple pathologies, including cancer. This review discusses recent advances in macrophage and neutrophil biology in healthy aging and cancer.

Historically, the immune environment was not considered an important target for breast cancer treatment. However, the association of lymphocytic infiltrates in triple negative and HER-2 over-amplified breast cancer subtypes with better outcomes, has provoked interest in evaluating the role of the immune system in the luminal B subtype that accounts for 39% of breast cancers and has a poor patient prognosis. It is unknown which immunosuppressive cell types or molecules (e.g., checkpoint molecules) are relevant, or where measurement is most informative. We hypothesize that a profound immunosuppressive tumor and/or lymph node milieu is prognostic and impacts on responses to therapies.